SECTION A: Pharmacologic Treatments

INTRODUCTION

Analgesics are drugs that relieve pain without significant loss of other sensations. The word analgesic is from the Greek an, without + algesis, sensation of pain. Opioid analgesics are the most effective and commonly used pharmacotherapy for moderate to severe pain.¹ Not all pain patients benefit from opioid therapy; however, more patients benefit from strong analgesics when the drugs are used as an element of multimodal therapy.

Opioids include all compounds that bind to opioid receptors; these include exogenous opioid receptor agonists and antagonists as well as the endogenous opioid peptides. The term opiate originally was used to describe a drug derived from opium but now includes the natural opium products (e.g., morphine), the semisynthetic derivatives (e.g., hydromorphone), and completely synthetic congeners (e.g., methadone).

The differences between exogenous opioids, such as morphine, and endogenous opioids, such as β-endorphin, do not justify differing terminology. Opioid accurately describes both types of compounds and is generally considered the preferred term in both clinical and scientific dialogue.

Narcotic, from the Greek narkotikos, benumbing, was originally used to describe opium derivatives. Today, narcotic has become a legal term that includes a broad range of sedating and potentially abused drugs, many of which are not related to opium. Because the word narcotic has negative connotations, physicians should not use it when talking with patients.

The last 30 years have seen a marked increase in our knowledge of the sites and mechanisms of action of opioids.¹ New analytical methods reveal pharmacokinetic (PK) data on the disposition and fate of opioids in humans. Recently elucidated opioid receptor-related genetic polymorphisms provide a greater understanding of how genetics can help predict responses to opioids.²

BRIEF HISTORY OF OPIOID ANALGESICS

The word opium is derived from the Greek opion, poppy juice. Opium is the milky exudation derived from the unripe capsules of the opium poppy, Papaver somniferum. Opium contains over 20 different alkaloids and has been used to control human discomfort for over five millennia. Opium was used clinically in the early days of European medicine, but it fell into disfavor because of toxic outcomes from nonstandardized forms that were not used with necessary care. Paracelsus repopularized the use of opium in the 16th century, and by the second half of that century, clinical use of opium was understood and adopted by physicians throughout the continent.

The French pharmacist Jean-François Derosne isolated a crystalline precipitate from opium in 1803, a mixture of morphine and narcotine. It was not until 3 years later that the German pharmacist Friedrich Wilhelm Sertürner isolated morphine, the pure alkaloid, and named it after Morpheus, the Greek god of dreams. Other opium alkaloids including papaverine and codeine were soon isolated, and within a few decades, the pure alkaloids replaced crude opium in clinical practice.

By the mid-19th century, many of the patent medicines sold as panaceas contained opioids. Steadily increasing federal and state control of opioids in the United States began with the passage of the Harrison Narcotic Act in 1914. The federal Bureau of Narcotics was created in the 20th century to address use of potentially abused drugs. In recent decades, political and law enforcement demands, rather than scientific or clinical findings, have defined the control system for opioid use in the United States. Creation of the Drug Enforcement Administration (DEA) by the Controlled Substances Act of 1970 assured that control of opioids and other controlled substances would be driven by law enforcement, not a patient care focus. Numerous initiatives, both within and outside of government, have worked to emphasize that opioids are important and frequently underused medications. These include the 1979 Report to the White House of the federal Interagency Committee on New Therapies for Pain and Discomfort, the 1985 report of the federal Interagency Committee on Pain and Analgesia,³ and the 1986 National Institutes of Health Consensus Development Conference Report titled “The Integrated Approach to the Management of Pain.”⁴ It may be that serious opioid underuse in the latter decades of the 20th century has been replaced by overuse in the early 21st century.⁵

OPIOID PHARMACOLOGY

It is not logical that the human body should contain specific receptors for alkaloids derived from a plant. The presence of endogenous opioids was postulated to explain the presence of opioid receptors before the endogenous substances were isolated. Cloning studies have identified three groups of endogenous opioid peptides; the enkephalins, endorphins, and dynorphins appear to function as neurotransmitters, neuromodulators, and neurohormones. These peptides are found within the central nervous system (CNS), adrenal medulla, nerve plexi, gastric exocrine glands, and intestines.

PHARMACODYNAMICS – MECHANISM OF ACTION

Opioid drugs manifest analgesic effects primarily by binding to and activating (agonizing) opioid receptors. Opioid receptors are found in the CNS and gastrointestinal (GI) tract and, to a lesser degree, in peripheral tissues. The interaction of exogenous opioid medications and opioid receptors mimics the interaction when endogenous opioid peptides (dynorphins, endorphins, enkephalins) bind with these same receptors.⁶ The three major classes of opioid receptors are the mu (μ), delta (δ), and kappa (κ) receptors.⁷ Sigma (σ) and epsilon (∊) receptors were formerly classified as opioid receptors because opioids can bind to them. However, neither is currently considered an opioid receptor because activation does not necessarily result in analgesia and neither of these receptor types is opioid-specific.

Opioid receptors are composed of glycoproteins found in cellular membranes. These receptors are coupled to G proteins that modulate potassium and calcium ion conduction⁸ (Fig. 68-1). At μ- and δ-opioid receptors, opioids open a potassium ion channel, increasing potassium conductance. Hyperpolarization inhibits neuronal activity. In contrast, κ-receptor activation inhibits calcium entry via a calcium ion channel. Activation of opioid receptors decreases transmission of signals from primary peripheral afferent sensory neurons to higher CNS centers, as well as the processing of the pain stimulus.

Administration of an opioid agonist activates opioid receptors, producing both analgesia and adverse effects. The three opioid receptor types have known subtypes (Table 68-1). Two μ subtypes have been elucidated. Activation of μ₁ leads to supraspinal analgesia, whereas μ₂ activation is associated with the adverse sequelae of opioid administration. Activation of κ and δ receptors produces spinal analgesia. However, κ₃ receptors are thought to mediate supraspinal analgesia.⁹ Activation of δ receptors may potentiate μ-receptor-induced analgesia, but no δ agonists are available for clinical use. Clinical implications of the δ- and κ-receptor subtypes are not fully understood.

Peripheral μ and κ opioid receptors in peripheral tissues can effect inflammation and exert antihyperalgesic activity.¹⁰ Topical and intraarticular opioids have been used to treat pain in soft tissue and joints. The clinical significance of the peripheral effects of opioids is not yet well understood.

Most opioids used as analgesics are µ agonists which bind primarily at µ opioid receptors (MORs) and also may bind to a lesser degree at κ receptors. Kappa opioid receptor ligands provide a few drugs; however, their clinical pharmacology is complicated by concurrent µ opioid receptor antagonist activity. Delta opioid receptor ligands have been in clinical investigation for years, but none was available for clinical use at the time of this writing. Most analgesics which are predominantly µ agonists also have some ability to bind at κ receptors. Some recent literature has suggested that µ agonists with some preferential κ binding capacity may be advantageous in visceral pain. Oxycodone displays that characteristic.¹¹

Opioid receptors generate nerve signals through a second messenger, cyclic adenosine monophosphate (cAMP), or an ion channel.¹ Alterations in the levels of cAMP and the transcription factor CREB (cAMP response element binding protein) during chronic morphine treatment are associated with numerous cellular changes, some of which can produce tolerance and physical dependence.¹² Molecular genetics approaches have used gene-targeting (knockout) technology to disrupt the gene that codes for each of the three types of opioid receptors. Mice given morphine that lack the µ opioid receptor (MOR-deficient mice) do not experience analgesia, respiratory depression, constipation, physical dependence, reward behaviors, or immunosuppression.¹³ µ opioid receptors are evident in the periphery following inflammation, in presynaptic and postsynaptic spinal cord dorsal horn sites, and in the brainstem, thalamus, and cortex. These locations constitute the ascending pain transmission system. These receptors also reside in midbrain periaqueductal gray, the nucleus raphe magnus, and the rostral ventral medulla. Those sites constitute the descending inhibitory system that modulates spinal cord pain transmission.¹⁴ µ agonists bind at MORs in the colon, causing opioid-induced constipation.¹⁵ Opioids also decrease presynaptic neurotransmitter release through calcium channel inhibition and increase potassium ion efflux, causing hyperpolarization of postsynaptic neurons and decreasing synaptic transmission. An additional mechanism of action of opioids is inhibition of GABAergic transmission within the CNS. The net effect is descending inhibitory circuit excitation.

Animal studies suggest that the reinforcing and rewarding properties of opioids (e.g., euphoria) that are associated with opioid abuse involve the mesolimbic dopamine system, not the supraspinal systems most prominently involved in the production of analgesia and physical dependence.¹⁶

CENTRAL NERVOUS SYSTEM OPIOID EFFECTS

Analgesia

Pain relief from µ agonist opioids is relatively selective; other senses are not affected. After opioid administration, some patients still perceive pain, but they generally report it as being less uncomfortable than it was before receiving the drug. Pain includes both sensory-discriminative aspects (e.g., perception of the location, type, and intensity) and an emotional dimension sometimes described as unpleasantness. Sensory-discriminative aspects are processed in the somatosensory cortex (SSC), while the affective component is processed in the anterior cingulate cortex (ACC). µ opioid receptors (MORs) are found in both of these areas of the brain. Non-opioid analgesics have dose-dependent analgesic effect ceilings; morphine-like opioids do not. However, dose-related adverse events produce a functional ceiling. These include sedation, obtundation, nausea, vomiting, and respiratory depression. The clinical dose needed for analgesia varies with the type of pain and among patients. As result, the most important clinical principle is titration of the opioid dose to response. Some patients will prefer less analgesia to retain a more intact sensorium; others prefer mental clouding if it is accompanied by pain relief.

Mood Effects

µ agonists can alter mood, including the relief of anxiety, euphoria, and—more commonly dysphoria. Chronic pain patients often report initial relief of depression, at least some of which may be due to decreased pain, which frequently proceeds to worsened depression in days to weeks. Reinforcing and rewarding properties of opioids in opioid abusers involve the mesolimbic dopamine system and differ from the systems which produce analgesia and physical dependence.

Nausea and Vomiting

µ agonists produce nausea and vomiting by stimulating the chemoreceptor trigger zone (CTZ) in the medullary area postrema. These adverse effects occur more frequently in ambulatory patients due to motion exacerbating vestibular sensitivity. Opioid-induced nausea and vomiting varies among drugs and among patients. Patients who cannot tolerate GI adverse effects from one opioid may tolerate another and find tapentadol better tolerated than pure µ agonists. Central antiemetics such as phenothiazines (e.g., prochlorperazine), a gastrokinetic drug (e.g., metoclopramide), or a 5-HT receptor antagonist (e.g., ondansetron) can be helpful.

Sedation

µ agonists are sedating and these effects are additive to those of other CNS depressants. Opioids are additive to respiratory depressants including alcohol, benzodiazepines, and other sedative-hypnotics. A central stimulant (e.g., methylphcnidate, modafinil) helps to counteract opioid sedative effects. Tolerance to opioid-induced sedation typically occurs to some degree within a few days.

Respiratory Depression

Respiratory depression with initiation of opioid pharmacotherapy for acute pain is potentially the most serious adverse opioid effect. The µ agonists act at brainstem respiratory centers. The effect is dose-related and sensitivity varies among individuals. Therapeutic morphine doses can depress respiratory rate, minute volume, and tidal exchange. As CO₂ accumulates, it stimulates central chemoreceptors, causing a compensatory increase in respiratory rate that masks respiratory depression. Respiratory depression and CO₂ retention produce cerebral vasodilation and increased cerebrospinal fluid pressure unless the PCO₂ is normalized by artificial ventilation. Respiratory depression occurs most commonly in opioid-naive patients after acute opioid administration and is associated with other signs of CNS depression, including sedation and obtundation. Tolerance to these effects develops rapidly, and the risk of the effects is relatively low with chronic opioid use in chronic pain management. Obstructive sleep apnea is common in obese patients and presents risk for opioid-induced respiratory depression, especially when the patients are sleeping. Opioids, and perhaps more so methadone, may induce potentially life-threatening central sleep apnea Respiratory depression can be reversed by prompt administration of the opioid antagonist naloxone. In patients chronically receiving opioids who develop respiratory depression, naloxone diluted 1:10 should be titrated carefully to prevent the precipitation of severe withdrawal symptoms while reversing the respiratory depression.

Three mixed agonist-antagonists, pentazocine, nalbuphine, butorphanol, and the partial agonist buprenorphine have different dose-response characteristics for their respiratory depression curves from the morphine-like opioids. While therapeutic doses of pentazocine produce respiratory depression equivalent to that of morphine, increasing the dose does not ordinarily produce a proportional increase in respiratory depression. Whether this apparent ceiling to respiratory depression offers any significant clinical advantage has not been determined. Naloxone reversal of the respiratory depression produced by buprenorphine requires relatively large doses (5-10 mg) and is delayed in onset.

Constriction of the Pupil

Opioids produce miosis through stimulation of the parasympathetic nucleus of the oculomotor nerve. Pinpoint pupils, respiratory depression, and loss of consciousness are the three signs of opioid overdose. All of these effects can be reversed with naloxone. Severe anoxia causes mydriasis.

Antitussive Effect

Opioids depress the cough centers in the medulla, depressing the cough reflex. Different mechanisms depress cough than produce analgesia. As a result, the dextrorotatory isomers of opioids (e.g., dextromethorphan), which do not bind to opioid receptors, are antitussive.

Hypothalamic Effects

Morphine alters hypothalamic heat regulation, lowering body temperature. Corticotrophin-releasing hormone (CRH) and gonadotropin-releasing hormone (GnRH) are inhibited, resulting in lowered luteinizing hormone (LH), follicle stimulating hormone (PSH), and adrenocorticotropic hormone (ACTH). Prolactin and antidiuretic hormone release are increased. Tolerance to these effects appears to occur.

Opioid-induced androgen deficiency (OPIAD) describes clinically meaningful decrease in testosterone levels that occurs in the majority of men receiving ongoing morphine or other potent µ agonist opioid pharmacotherapy. Worsening of pain, depressed mood, and refractoriness to treatment are common in such patients. Trials of androgen supplements have been helpful and this phenomenon also appears to occur in women, presumably due to progesterone suppression.

Central Nervous System Excitation

In addition to being CNS depressants, opioids can be excitatory. Normeperidine, a major metabolite of meperidine produces anxiety, tremors, myoclonus, and generalized seizures when it accumulates with repeated dosing. Naloxone does not reverse, and may even exacerbate, this hyperexcitability. Other high-dose µ agonists can produce multifocal myoclonus in opioid-tolerant patients.¹⁸

CLINICAL USES

Opioids remain the most effective analgesics available; as such, they are essential in clinical medicine for the management of moderate to severe pain in many cases. However, the misuse of prescription opioids resulting in morbidity and mortality has produced controversy over opioid availability and control.¹⁹ Opioids are clinically useful in treating diarrhea and GI hypermotility because activation of opioid receptors in the intestines slows peristalsis. Opioids decrease respiratory activity which can be useful in anesthetized patients and to help manage air hunger, especially in end-of-life care. Opioids also can lessen anxiety and excitation and induce a feeling of well-being.

Much opioid pharmacology learned by health care professional students is based on studies conducted in lower animals or isolated tissues. Those rarely address the profound cognitive effects of pain and analgesia that greatly influence outcomes of opioid therapy in humans. Serious misunderstanding among health care providers results from failure to recognize the great differences between acute opioid toxicity and that seen with long-term therapy. Incorrect assumptions and beliefs about opioid toxicity, addiction potential, and tolerance to analgesic effects have led to poor use of these effective drugs in many clinical settings. This has led to widespread opiophobia, the irrational and undocumented fear that appropriate use of opioids causes addiction.²⁰

OPIOID AVAILABILITY AND USE

Balance in opioid availability and use is essential for good patient care outcomes and the public health. Well-designed guidelines have helped to define that balance.^21-23

Opioid pharmacotherapy for chronic nonmalignant pain was considered controversial by many physicians well into the 1990s despite numerous published studies that documented the safety and efficacy of opioids in the management of a variety of chronic nonmalignant pain states, such as neuropathic, myofascial, arthritic, and osteoporosis pain.²⁴ In 2002, the Federation of State Medical Boards of the United States published “Model Policy for the Use of Controlled Substances in the Treatment of Pain.”²⁵ This authoritative publication clearly documents that opioids have a place in the management of many patients’ chronic nonmalignant pain.

Many physicians are more willing to use opioids in patients with cancer pain than noncancer pain. The fact that opioids are seriously underused was underscored by a study of opioid prescribing for cancer pain patients that was published in the Journal of the American Medical Association in 1998.²⁶ Researchers evaluated the records of 13,625 cancer patients discharged from hospitals to Medicare or Medicaid certified nursing homes during the 4-year period 1992 to 1995 in five states. A total of 4003 patients reported and had multiple factors independently associated with daily pain. Only 26% of patients received morphine or another opioid considered to be on level 3 of the World Health Organization (WHO) analgesic ladder²⁷ (Fig. 68-2). Only 32% of patients received a step 2 analgesic, and 26% received only acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) for analgesia.

The WHO analgesic ladder that was developed to guide analgesic therapy for cancer patients in developing countries has been shown to be applicable in most pain management in most societies. This approach describes three levels of analgesia. It suggests that pharmacologic management of mild to moderate pain should include a NSAID or acetaminophen unless there is a contraindication as a first step. When pain persists or increases, add an opioid as the second step. The third step consists of increasing the opioid dose to treat persistent moderate to severe pain. This is not a stepped approach in which prior steps must be tried before initiating more aggressive therapy. Analgesia should be started at the level appropriate for the patient's pain. For cancer pain, a fourth step including palliative radiation and chemotherapy, nerve blocks, and various other modalities exists in developed countries.

Equianalgesic dose tables often use parenteral morphine 10 mg every 4 hours as the standard for comparison. Equianalgesic doses are listed in Table 68-2. The dose tables will not apply to all patients because of interpatient variances in response to opioids. The tables do provide an approximation of equally effective doses, but patients must often be retitrated to response when the opioids they are taking are changed. It is important to differentiate among the pure µ-opioid receptor agonists, mixed agonist-antagonists (which are κ-opioid receptor agonists and either antagonistic or neutral at µ receptors), and partial agonists. There is no proven difference in analgesic activity among the pure µ agonists. Greater potency does not imply higher activity. Potency differences simply mean that different amounts of drug must be used to obtain the same activity. PK differences can be clinically important.

PHARMACOKINETICS

Pharmacokinetic parameters to consider include peak serum level (C_max), time to peak serum level (T_max), and elimination half-life (T_1/2). Oral-to-parenteral dose ratios also vary among opioids (Table 68-3). Also, differences in metabolism (biotransformation) may sometimes make one opioid preferable to another, especially in a patient with impaired metabolism or elimination. Opioids may be long acting due to inherent pharmacologic factors, for example, methadone, levorphanol, or a pharmaceutical formulation. Each type has advantages and disadvantages. The PKs of commonly used opioids have been well described at all phases of human life.^28-30

CURRENTLY AVAILABLE OPIOIDS

Opioids can be administered by oral, intramuscular, intravenous, subcutaneous, rectal, sublingual, transdermal, transmucosal, epidural, and intrathecal routes. The intramuscular route is now discouraged because it is painful and the subcutaneous route provides similar PK. Table 68-4 lists commercially available µ-agonist opioids. While several new dosage forms of previously available opioids were introduced in recent years, only one new opioid chemical entity per se has become available in the past quarter century. Tapentadol is a mixed µ agonist, norepinephrine reuptake inhibitor. Because these two mechanisms are synergistic, tapentadol can provide comparable analgesia to other potent opioids with less µ agonist activity, resulting in a fewer GI adverse effects. In some patients who experience GI intolerance to traditional opioids, this can be an advantage.¹⁰

The µ agonists can be divided into three categories based on their duration of action: short-acting, long-acting, and ultra–short-acting. Morphine and other opioids with short half-lives require frequent administration to maintain analgesia. Immediate-release morphine products provide about 4 hours of pain relief and need to be dosed every 4 to 6 hours to maintain analgesia. Pharmaceutical sustained-release formulations (e.g., MS Contin, Oramorph-SR, Kadian, Avinza, OxyContin, Opana ER, Nucynta ER orally; Duragesic transdermally), require less frequent administration. Methadone is a pharmacologically long-acting opioid, allowing dosing every 8 hours for analgesia at a much lower cost than most pharmaceutically long-acting opioids. Because methadone has atypical PK, it should be used by physicians familiar with its pharmacology and in patients who are adherent to prescribed regimens. Deaths have resulted from overly rapid titration of methadone and possibly due to increased risk of central sleep apnea.

The fentanyl series is highly lipophilic, which allows these drugs to be used differently from the other µ agonists. Their rapid onset of action facilitates use as preoperative and intraoperative agents. High lipophilicity facilitates transdermal and subcutaneous administration. When administered through or under the skin, these medications deposit in subcutaneous fat. Medication is released from the fat slowly. Conversely, when these medications are administered transmucosally or sublingually, they are rapidly absorbed due to the lack of the buccal and sublingual fat. Rapid absorption following transmucosal and sublingual administration makes these drugs useful in managing breakthrough pain.

OPIOID DOSING

Although most µ-opioid agonists are similar pharmacodynamically, they differ in PK properties, which effects dosing. All except codeine normally provide the same level of analgesia when dosed appropriately on average. For several reasons, including genetic polymorphism, some patients respond better to some opioids than others. Clinical trial is the only way to determine a preferred alternative if a patient does not respond as expected to the initial choice. Pharmacokinetic properties and controlled-release formulations play major roles in the drugs’ fate in the organism. As long as an opioid-responsive noxious nociceptive stimulus is present, these drugs should be used on a regular schedule or time-contingent basis. Undertreated acute pain predisposes to chronic pain syndromes.³¹ Untreated or undertreated pain causes repeated stimulation of the CNS. Repeated stimulation of the afferent nociceptive neurons, producing the phenomenon known as physiologic windup, can sensitize these neurons and cells in the dorsal horn of the spinal cord, resulting in neuronal plasticity.³² Such sensitization can induce neurologic changes that last long after the initial insult has healed. Neuronal plasticity, or changes in the CNS, may lead to hyperalgesia. Windup is the progressive increase in the frequency of elicited action potentials seen in neurons as a result of a slowly repeated stimulus of C fibers.³³ Long-term potentiation (LTP) is a high-frequency brief stimulus that increases the efficiency of synaptic transmission.³⁴ These processes lead to hyperalgesia as a consequence of central excitability. The use of around-the-clock opioids often breaks the cycle of pain and can decrease or eliminate the centrally mediated processes that complicate pain control. Thus, it may take less drug to prevent the recurrence of pain than would be required to treat recurring pain.

Morphine and other pure opioid agonists can provide analgesia in most acute and chronic malignant pain patients and many chronic nonmalignant pain patients. There is no a priori maximum dose for any pure µ agonists. Patients require individual titration of medication regimens. Morphine dose requirements for comfort following similar noxious stimuli may vary 50- to 100-fold among chronic malignant pain patients,³⁵ and 10- to 20-fold among acute pain patients.³⁶

In addition to regularly scheduled opioid doses, supplemental doses should be available for management of breakthrough pain. Breakthrough pain can be defined as transitory increases in pain greater than moderate intensity, occurring in addition to baseline pain of moderate or less intensity.³⁷ Breakthrough pain regimens should be based on the background (time-contingent) dose, not on fixed doses. Sufficient rescue doses of the opioid should be available to the patient as immediate-release dosage forms to provide comfort when breakthrough pain occurs. Incidental pain often occurs predictably when a patient ambulates, gets tired, or undergoes medical procedures. In such cases, an additional dose of an oral, immediate-release dosage form should be administered to provide effective levels about one-half hour before the anticipated pain increase. For unpredictable breakthrough pain, a typical rescue dose is one-half of the every 4-hour scheduled dose (1/6 of the every 12-hour scheduled controlled-release dose) permitted every 2 hours as needed. When a patient with chronic pain requires more than two to three rescue doses for more than 2 to 3 days in succession, an increase in the time-contingent dose should be considered.

When increased doses are warranted, increase the dose as a percentage of the current regimen, not a set number of milligrams. Increases of 50% should be made as soon as steady-state serum levels are achieved (5 half-lives, which is equal to ~10 hr for morphine) after 5 days of scheduled opioid therapy. An increase from 30 mg every 4 hours to 45 mg every 4 hours would be appropriate. If the inadequate dose is 300 mg every 12 hours, the increase should be to 450 mg every 12 hours.

Physicians should carefully evaluate concerns of increased pain or diminished analgesic effect in patients whose analgesia was adequate before simply increasing the opioid dose. Clinical tolerance to opioid analgesia in itself is uncommon once comfort has been achieved and maintained for a few days. Ineffective analgesia often results from factors that increase pain or compromise analgesic efficacy. These include progressive disease, new disease, increased or excessive activity, poor adherence, changed medication formulation or brand, drug interactions, and opioid addiction or diversion.

Methadone affords analgesia for 8 hours once steady-state serum levels are achieved. Less frequent dosing protects against opioid withdrawal but does not provide ongoing analgesia. While low methadone serum levels can protect from withdrawal for 24 hours or more following a single dose, the levels are too low after 8 hours to provide analgesia. Because of the long and variable half-life of methadone, physicians should exercise caution. Patients may achieve adequate analgesia initially, but with continued use they may become toxic due to accumulation of methadone and its metabolites (Fig. 68-3). Methadone is not recommended in acute pain due to its extended half-life.

ROUTES OF ADMINISTRATION

Most currently available µ agonists can be given orally, rectally, parenterally, transdermally, and transmucosally. The mixed agonist-antagonists are available in parenteral dosage forms. Pentazocine also is available in an oral tablet, and butorphanol in a nasal spray. For most patients taking time-contingent opioids, oral dosage forms are preferred agents. The oral route is easy to use, is relatively inexpensive, does not signal increasing disease to the patient or family, and is effective. Incomplete bioavailability is easily overcome by increasing the dose. The only advantage of parenteral over oral administration for a patient able to take a drug orally is more rapid onset. The time difference to analgesic onset and peak levels between oral administration and intramuscular or subcutaneous injections is often negligible. With appropriate scheduling, each dose of opioid can be administered sufficiently in advance of the prior dose to prevent recurrence of pain.

Rectal administration is an option for patients unable to tolerate oral drugs, especially in short-term and terminal care. Hydromorphone, morphine, and oxymorphone are commercially available in rectal suppositories. Controlled-release oral morphine tablets have been used effectively via the rectal route³⁸ (Table 68-5). Mucosal irritation may occur in fewer patients with rectally administered oral controlled-release morphine tablets than with commercial morphine suppositories.³⁹ No local adverse effects were noted in a report of controlled-release oral morphine administered rectally.⁴⁰ Suppositories and tablets should be inserted just above the anal sphincter to minimize first-pass metabolism. The inferior and middle rectal veins do not drain into the portal circulation as do the superior rectal veins. Administration higher into the rectal vault could induce a partial first-pass effect, which would lessen the effectiveness of the dose. As with any rectal administration, patients receiving opioids by this route should lie quietly on their sides for about 15 minutes after administration to aid absorption and minimize risk of rectal expulsion of the dose. Rectal administration of oral liquids may be an option in some patients limited by acceptable rectal fluid volumes and esthetics.

An effective and noninvasive route for opioid administration is transdermal. Fentanyl and butorphanol are available for transdermal administration. Transdermal fentanyl patches are indicated for management of chronic pain in patients tolerant to the respiratory depressant effects of opioids. They provide 72 hours of clinically effective CNS opioid levels in most cases, but some patients obtain only about 48 hours of relief from a patch. Although the patches are more expensive than oral dosage forms, they are a convenient and cost-effective alternative to parenteral opioids. Transdermal fentanyl can be used by patients unable or unwilling to use oral or rectal opioids. The patch can also be useful for patients with noncompliant behaviors, for example, patients who cannot remember to take their opioid. As mentioned previously, this dosage form can be problematic in patients who require rapid-dose titration or have rapidly changing analgesic requirements.^41,42 Transdermal buprenorphine patches available in 5, 10, and 20 µg/hr strengths provide up to 7 days of continuous analgesia.⁴³

The subcutaneous route is an easy and inexpensive way to administer opioids. It is common in palliative care, where it provides a good alternative to the intravenous route. Intravenous opioid administration is especially useful following surgery and trauma. Intravenous patient-controlled analgesia (PCA) is routinely used in many acute settings, especially for postoperative analgesia. While intravenous opioids are warranted when GI function is limited (e.g., postoperative ileus), the intravenous route can negatively reinforce the sick role in patients with chronic pain and those requiring end-of-life care. The major advantage of intravenous PCA over regularly scheduled injections is the sense of control PCA provides to the patient. PCA offers no pharmacologic advantage over regularly scheduled oral opioids for patients able to tolerate oral medications.⁴⁴

Spinal administration of opioids is warranted in a small number of patients. It avoids the toxicity associated with the systemic delivery of these medications. The epidural and intrathecal routes each have advantages and disadvantages. Epidural administration allows opioid placement at any dermatomal level and does not require puncturing of the dura. Larger doses, however, are required and systemic effects may occur with epidural administration, increasing the risk of adverse effects. For morphine, intrathecal doses are only one-tenth of those needed for an equianalgesic epidural dose. Intrathecal administration requires puncturing of the dura and placing the drug closer to the spinal cord receptors. Drawbacks to intrathecal use include increased potential for meningitis and risk of postdural puncture headaches. Dose-related problems associated with spinal analgesia include pruritus, urinary retention, and delayed respiratory depression. Spinal analgesia is discussed in depth in Chapter 81.

Sublingual opioid administration has been used extensively in palliative care. Advantages include ease of administration, low expense (with oral, not parenteral, solutions), avoidance of hepatic first pass, and rapid onset of action (~5-15 min). Disadvantages include relatively low bioavailability, potential for poor taste acceptance, and the need to avoid drinking anything for about 15 minutes following administration. Simple aqueous solutions are most appropriate for this route. The volume of a dose should not exceed 1 mL to minimize medication trickling down the throat. If a larger amount of medication is needed than will readily dissolve in 1 mL of water, a second dose can be given after 5 to 10 minutes. In a study of the percentage of sublingual opioid absorbed after 1 mL of an aqueous solution was held in the mouth for 10 minutes at pH 6.5, absorption was greater for lipophilic than hydrophilic opioids. Results from that study are listed in Table 68-6. As the mouth pH increased, absorption increased. Opioids often taste bitter, but many patients find overly sweet solutions even less palatable. Mild citrus or bland flavors are usually most acceptable. Changes in the oral mucosa, stomatitis, increased keratinization, decreased salivary flow, and changes in salivary pH due to disease, trauma, radiation or chemotherapy, as well as the overall condition of the mouth, influence absorption from sublingual, buccal, and oral transmucosal administration.

Nebulization into the lungs and intravaginal use of oral tablets and rectal suppositories have been reported. Nebulized morphine can be useful in dyspnea (air hunger), especially in terminally ill patients.⁴⁵ However, systemic opioids may be required to effectively treat cough.⁴⁶ Because of the unpredictable bioavailability resulting from vaginal delivery, this route is not recommended.⁴⁷ Intrastromal administrations have been used with reported success by some hospice programs. Drug level data from this route have not been reported.

DRUG INTERACTIONS

Opioids interact with a variety of medications (Table 68-7). Most opioid drug interactions are a consequence of additive effects, that is, pharmacodynamic interactions. Increased sedation can be seen when opioids are administered with alcohol, benzodiazepines, butyrophenones, phenothiazines, sedative hypnotics, and tricyclic antidepressants. Midazolam may decrease the effect of fentanyl. Antinociceptive activity may be impaired by benzodiazepine administration from inhibition of the descending inhibitory control pathways.⁴⁸

Methadone withdrawal has been precipitated by a number of agents known to induce hepatic microsomal enzymes.⁴⁹ This PK interaction increases methadone metabolism. Opioids can inhibit metabolism of other agents, leading to increases in serum levels of affected drugs. Desipramine plasma levels may be increased by coadministration with methadone or morphine.⁴⁹

PRINCIPLES OF OPIOID USE

A World Health Organization (WHO) Expert Committee defined five principles of opioid use in 1986 to manage cancer pain in developing countries. Those principles have been validated numerous times in undeveloped, developing, and developed countries, including the United States.^50-58 Federal clinical practice guidelines published by the U.S. Department of Health and Human Services in the 1992⁵⁹ and for cancer pain by the government in 1994⁶⁰ and by the American Pain Society in 2005⁶¹ validated these principles in both acute pain and chronic cancer pain. These principles may be summarized as:

1. Use oral or other noninvasive routes whenever possible.

2. Individualize doses by titrating to response.

3. Select analgesics according to needs as described on the analgesic ladder.

4. Maintain effective drug levels in the body as long as there is a noxious stimulus.

5. Use indicated adjuvants.

The usefulness of this approach has been studied in over 2100 cancer patients treated over a period of 10 years for a total of 140,478 treatment days. Drugs on step 1 of the WHO analgesic ladder provided adequate analgesia for only 11% of the days, step 2 for 31% of the days, and step 3 for 49% of the treatment days. Fifty-six percent of the patients received morphine. Co-analgesics, including antidepressants, anticonvulsants, and corticosteroids, were used on 37% of the treatment days and drugs for other symptoms, such as laxatives, were used on 79% of the treatment days. In their final days of life, 84% of the patients rated their pain as moderate or less.⁵⁷

A 1998 study of over 4000 cancer patients with documented daily pain who were residents in over 1400 nursing homes in five Midwestern American states revealed serious underuse of opioids in managing pain. Sixteen percent received only acetaminophen or an NSAID, 32% received WHO analgesic ladder step 2 drug therapy, and only 26% received morphine. Fully 26% of these patients received no analgesia.²⁶ Although the WHO and AHCPR guidelines on use of opioids have been available for so long, it is difficult to understand how such inadequate use of these drugs continues.

MYTHS AND MISCONCEPTIONS

Many health care professionals subscribe to false beliefs about opioids. Unnecessary fears of addiction, dependence, tolerance, and toxicity often deter prescribing and taking of these important medications.

ADDICTION AND DEPENDENCE

Until recently, much of what was known about opioid addiction was based on the experience of drug abusers, not patients. Opioids more commonly cause dysphoria than euphoria among opioid-naive individuals. Patients in pain seek comfort, not a drug-induced high. Patients with a recent (not necessarily remote) history of substance abuse and certain psychiatric disorders, notably bipolar disease and personality disorders, may be at greater risk of drug misuse. Studies of the incidence of iatrogenic opioid addiction show that this phenomenon is uncommon. The Boston Collaborative Drug Surveillance Program study reported only four cases of iatrogenic addiction among 11,882 patients without prior history of substance abuse who received opioids for a broad range of indications and were followed for up to 2 years.⁶² A national survey of over 10,000 burn patients without prior histories of drug abuse who received opioids for extended periods revealed no cases of addiction.⁶³ Only 3 of 2369 chronic headache patients, most of whom had access to opioids, abused the analgesics.⁶⁴ Although the studies were retrospective and may have underestimated the true prevalence of iatrogenic addiction, they certainly support the contention that this phenomenon is far less common than many physicians believe.

Addiction was defined by an international panel in 1988 as the compulsive use of a substance resulting in physical, psychological, or social harm and continued use despite that harm.⁶⁵ More recently, addiction was defined by a consensus committee of the American Pain Society, the American Academy of Pain Medicine, and the American Society of Addiction Medicine as a primary, chronic, neurobiologic disease with genetic, psychosocial, and environmental factors influencing its development and manifestations that is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving.⁶⁶ Drug-seeking behavior does not in itself indicate addiction.

Pseudo-addiction has been defined as drug-seeking behavior due to inadequate analgesia, not substance abuse.⁶⁷ The American Society of Addiction Medicine said in its April 1997 Public Policy Statement that “Individuals who have severe, unrelieved pain may become intensely focused on finding relief for their pain. Sometimes, such patients may appear to observers to be preoccupied with obtaining opioids, but the preoccupation is with finding relief of pain, rather than using opioids, per se. This phenomenon has been termed pseudoaddiction.”⁶⁸

Dependence is defined as a physiologic phenomenon characterized by an abstinence syndrome upon abrupt discontinuation, substantial dose reduction, or administration of an antagonist.^65,66 Dependence occurs predictably among patients who take opioids on a regular basis for more than a few days. It also occurs predictably among patients taking steroids and many other common drugs. Opioid dependence can usually be ended by tapering the dose over 5 to 10 days when the drug is no longer needed. It should not be a barrier to use of the drugs when they are indicated. Neither dependence nor tolerance is indicative of or a predisposing factor to addiction.

TOLERANCE

Tolerance to opioids is widely misunderstood. Three distinct types of tolerance occur with opioids. Tolerance to the respiratory depressive effects and other manifestations of CNS depression normally occurs within 5 to 7 days of continuous, regularly scheduled opioid use. Such patients are referred to as opioid-tolerant. Tolerance to the constipating effects of opioids does not occur. Activated µ-opioid receptors in the colon inhibit peristalsis. Stimulating laxatives, (e.g., senna, bisacodyl) are needed to induce colonic emptying. Stool softeners alone are not effective. Because of the risk of severe constipation and fecal impaction, prophylaxis with stimulating laxatives may be indicated when opioid therapy is started.⁶⁹ However, about one-half of patients with severe opioid-induced constipation do not respond adequately to stimulating laxatives with increased water and fiber intake.⁷⁰ The peripherally acting µ opioid antagonist methylnaltrexone is now available to manage the potentially severe adverse effect of opioid pharmacotherapy.⁷¹

It often is necessary to increase the opioid dose over the first few days or week of therapy while finding the effective dose. Tolerance to analgesia does not occur in most patients once the effective dose of opioid is identified and administered regularly. Neither up nor down regulation of opioid receptors occurs with regularly scheduled dosing. Most patients remain comfortable on a consistent opioid dose unless another variable occurs. When an otherwise stable opioid dose ceases to be effective, pseudotolerance due to increasing or new pathology, excessive physical activity after the pain decreases, drug interactions, noncompliance, or other nonpharmacologic factors should be considered.⁷²

MULTIPLE PAIN COMPLAINTS

Many physicians conclude that patients are opioid abusers when the patients have complaint of new pain after their initial pain is controlled. In a study of 955 advanced cancer patients, 34% experienced two or more different types of pain, and 80% reported pain resulting from two or more different causes.⁷³ Similar findings have been reported for AIDS patients.⁶⁹ More severe pain tends to mask less intense pain. When the former is effectively treated, masked pain that requires additional treatment often becomes evident.

SAVE OPIOIDS UNTIL THEY ARE REALLY NEEDED

A common belief of patients is that use of opioids relatively early in the course of a progressive disease will render them less useful later, when they may be needed more. That is not true. Pure µ opioids are effective over a broad clinical dosage range (Fig. 68-4). When pain increases, doses can be increased without loss of effectiveness.

OPIOIDS ARE EFFECTIVE FOR ALL TYPES OF PAIN

Opioids are effective analgesics for most nociceptive and much neuropathic pain. However, all pain is not opioid-responsive. Some pain that is opioid-responsive should not be managed with opioids, for example, constipation pain. The underlying cause of the pain should be treated before considering the sole use of opioids to control it. Examples of this include neuropathic pain, for which tricyclic antidepressants, anticonvulsants, and nerve blocks may be indicated; painful infectious cysts, for which incision and drainage followed by anti-infectives may be indicated; and GI spasm, for which anticholinergic agents may be most effective.⁷⁴

PARENTERAL OPIOIDS ARE MORE POTENT AND EFFECTIVE THAN ORAL DOSES

Many patients believe that parenteral opioids are more effective than analgesics administered by oral or other noninvasive routes. As discussed earlier, this is not true. Furthermore, use of parenteral routes signals advancing disease to many patients and may be psychologically disadvantageous. Potency is commonly misunderstood. Potency indicates only the amount of drug needed for effect. For example, 10 mg of oral morphine is approximately equal to 1.5 to 2 mg of oral hydromorphone. Hydromorphone is therefore about five times more potent, but no more effective, than morphine. When patients ask for more potent drugs, they usually mean more effective drugs.

DOSE INCREMENTS SHOULD BE CONSERVATIVE

Fear of opioids causes many physicians to use conservative dose increments. This can lead to treatment failure. Opioid doses should be increased to response. The appropriate increment is normally 50% of the dose, and this can be increased every five half-lives (twice a day for morphine). This percentage of increase applies no matter what the prior dose. When a patient knows that the opioid dose has been increased but adequate analgesia does not result, anxiety often increases. This increases the pain perception, which in turn increases the opioid dose requirement further. It is often better to err slightly in the direction of too much than too little opioid. Initial sedation may be advantageous when a patient is very anxious and experiencing a sleep deficit from the pain.

OPIOIDS PREVENT SAFE DRIVING DUE TO IMPAIRED JUDGMENT AND PSYCHOMOTOR FUNCTION

Opioids can markedly impair judgment and psychomotor function when therapy is initiated. Similar adverse effects can occur when doses are increased. But once a patient has been continuously receiving opioids on a regular schedule for about a week, these effects usually diminish markedly. There was no significant difference in the number of motor vehicle crashes that involved 24 drivers who were taking opioids on a regular schedule for long-term pain management than among the general population of Finland.⁷⁵ A systematic review of the world literature confirmed this finding.⁷⁶ If the patient is experiencing no observable opioid-induced impairment and the opioid dose has been consistent for a week or more, the patient can usually drive or carry out other normal functions safely. When the dose is increased, however, the patient should refrain from those activities for about a week and until any impairment due to the increased dose resolves.

CONCLUSION

Opioids are important and commonly underused analgesics. However, there is real concern about misuse and overuse of prescribed opioids as well. Health care professionals, patients, and care givers often harbor irrational fears about these drugs. Opiophobia has been defined as “irrational and undocumented fear that appropriate use of opioids causes addiction.” As a result, opioids are often underprescribed, underdosed, taken irregularly in spite of instructions to the contrary, and stopped abruptly. Inappropriate beliefs about opioids have been documented among physicians,⁷⁷ nurses,⁷⁸ and pharmacists.⁷⁹ Societal barriers to the use of opioids are now being refuted by professional organizations and regulatory agencies. Concurrently, concerns about opioid misuse, overuse, and diversion are increasing. Physicians must use opioids with caution, but should not hesitate to use these important medications when they are clinically indicated. It is tragic that many physicians avoid opioids in their practices due to concerns about regulatory oversight; this works to the detriment of their patients. Unlike nonsteroidal anti-inflammatory drugs and even acetaminophen, long-term opioid use rarely causes end-organ toxicity.

Opioids delivery systems including oral controlled-release, iontophoretic, implanted, transdermal, and transmucosal dosage forms are currently under development. Combination dosage forms of opioids with other drugs also are being investigated. Some of these new forms may make opioid analgesia easier. However, excellent analgesia can be provided with the drugs and dosage forms currently available. Pain physicians can and should work to overcome opioid myths and misconceptions and should encourage appropriate use of opioids when they are indicated.

REFERENCES

INTRODUCTION

Similar to treatments that carry substantial risks and must be used with great care, the drug group collectively known as opioid analgesics can be therapeutically desirable for treating severe acute pain, pain at the end of life, and other pain conditions in which the benefits of use outweigh the potential risks. Despite the need for cautious use of opioids, prescribing has become pervasive and excessive. Although opioids are one of many legitimate and diverse options for treating pain, they represent a large share of risk.

Chronic pain is a common reason patients seek medical care. A significant challenge in treating patients with chronic pain is that no perfect method exists to assess the existence or intensity of pain that a patient experiences. It remains impossible to prove that a patient does or does not have pain or pain relief. Prescribers with limited background in pain management and scarce resources may feel pressured to lean too heavily on opioids as the first or only option for chronic pain management. For many prescribers, pain management and opioids have become synonymous, as if prescribing opioids is equivalent to adequate pain management or withholding them were equivalent to undertreatment.

Over the past decade, interrelated public health trends have developed as a result of the prevalence of and difficulty in treating patients with pain syndromes. First, increased clinical attention was directed across all medical specialties to the undertreatment of pain. This was followed by more frequent and escalating prescribing of opioids. The improved comfort and quality of life seen with aggressive opioid therapy for patients with terminal cancer was extrapolated to patients with chronic pain. Moreover, predictions of safety with chronic use of opioids were founded on low-quality data. The increased availability of opioid medications was followed by a shift in patterns of drug abuse from illicit to prescription drugs—most notably a dramatic increase in diversion and nonmedical use of opioid pain medications within the United States. A paradigm shift is under way that emphasizes safety and a more limited role for opioids in overall chronic pain care. Major policy changes have also emerged that every prescriber should be well aware of.

Addiction and abuse are pivotal concerns associated with using opioids. However, opioids have a wide range of adverse effects that can result in serious morbidity and mortality. Additionally, opioid medications are not universally effective for all types of chronic pain or all patients.¹ A major risk associated with opioids is respiratory depression resulting from unintended overdose. The risk for respiratory depression is heightened in older persons, those with mental illness, those with impaired renal or hepatic function, and individuals with cardiopulmonary disorders such as chronic obstructive pulmonary disease (COPD), congestive heart failure (CHF), and sleep apnea. Patients who combine opioids with other respiratory depressants such as alcohol, benzodiazepines, barbiturates, or sedative-hypnotics are also at increased risk for respiratory depression. Chronic opioid use also has a negative impact on endocrine function and possibly heightened fracture risk related to effects on bone metabolism,^2,3 potential birth defects in unborn children,⁴ and potential facilitation of tumor growth in cancer.^5,6,7

Prescriptions for opiates increased from 76 million in 1991 to 207 million in 2013; the United States was the largest consumer of opioid medications.⁸ Hydrocodone is the most prescribed drug in the United States, which consumes 99% of the world's supply.⁸ Factors that contribute to the increase in opioid prescribing include the introduction of long-acting formulations and novel delivery systems, as well as prescriber concerns about the dangers of non-opioid analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDS) and acetaminophen. These factors are seen in a much different light as the United States confronts an epidemic of opioid prescription abuse:

• Between 1998 and 2008, the rate of opioid abuse increased 400%.⁹

• More than 6 million Americans abuse prescription drugs—more than the number estimated to abuse cocaine, heroin, hallucinogens, and inhalants combined.¹⁰

• Emergency-department visits related to pharmaceutical opioids doubled between 2004 and 2008.¹¹

• Between 1998 and 2012, a tenfold increase was noted in drug treatment admissions for prescription opioids.¹²

• The number of deaths nationwide attributable to prescription opioid analgesics nearly quadrupled between 1999 and 2012.¹³

• From 1999 to 2005, the number of poisoning deaths mentioning methadone increased 468%.¹⁴

• Drug abuse is now a leading cause of accidental death in America, exceeded only by car crashes; in many states opioid overdose is the leading cause of accidental death.¹⁵

These alarming statistics have led some to propose extreme measures to curb opioid misuse. A number of physicians have chosen to stop treating chronic pain in patients altogether even though the problem of unrelieved pain is significant. In the United States, the incidence of chronic pain is estimated at 100 million people,¹⁶ greater than that of diabetes, heart disease, and cancer combined.^17,18 The cost of treating patients with chronic pain is estimated to be up to $635 billion.¹⁶

Regardless of the need for comfort, prescribers must weigh the benefits versus the risks of pain management. Clinical guidelines, policy statements, and organizational goals generally accept the following principles of pain treatment:¹⁹

• Pain management is integral to good medical practice for all patients.

• Opioid therapy to relieve pain and improve function is a legitimate medical practice for acute and chronic pain of both cancer and noncancer origin.

• The use of opioids for other than legitimate medical purpose poses a threat to the individual and to society.

• Prescribers have a responsibility to minimize the potential for the abuse and diversion of controlled substances.

UPDATED POLICIES AND REGULATIONS REGARDING OPIOID PRESCRIBING

The Food and Drug Administration (FDA) announced in September 2013 that it would require more specific language regarding patient risks in the labeling of extended-release/long-acting opioid medications.²⁰ Manufacturers are now required to include language to emphasize potential for misuse and abuse, neonatal opioid withdrawal syndrome (NOWS), addiction, overdose, and death.²¹ In addition to new labeling requirements, the FDA released strong recommendations advising prescribing physicians to carefully weigh the risks and benefits of opioid medications for the treatment of chronic pain, stopping short of recommending that opioid medications not be used for chronic pain.

THE NEW FDA LABELING FOR LONG-ACTING/EXTENDED-RELEASE (LA/ER) OPIOIDS WILL CHANGE IN THE FOLLOWING WAYS:

• “Indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate.”

• LA/ER opioids are not intended for use as an “as-needed” pain reliever.

• Other, less potentially addictive, treatment options should be considered first [“Because of the risks of addiction, abuse and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, LA/ER opioids should be reserved for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate”].

• Patients in pain should be assessed not only by rating on a pain intensity scale but also based on a more thoughtful determination that their pain—however it may be defined—is severe enough to require daily, around-the-clock, long-term opioid treatment, and for which alternative treatment options are inadequate.

• The new labeling will provide increased detail and elevate the risk of neonatal opioid withdrawal syndrome (NOWS) to the most prominent position in labeling—a boxed warning. It will emphasize the symptoms of NOWS, including poor feeding, rapid breathing, trembling, and excessive or high-pitched crying [FDA-approved labeling previously described the effects on newborns of exposure to these drugs while in the mother's womb and warned against use by women during pregnancy and labor and nursing.].

• Manufacturers of LA/ER opioids will be required to fund and conduct longer-term post-market studies and trials of LA/ER opioid pain relievers that evaluate long-term use and assess known serious risks, including misuse, abuse, addiction, overdose, death, and increasing sensitivity to pain.

• Patient/consumer education will be required that will target risk reduction. Educational materials for patients and health care professionals (HCPs) will be modified to reflect new labeling for ER/LA opioids and LA/ER opioid manufacturers will revise a paper handout that patients will receive with their prescription.

• The ER/LA Opioid Risk Evaluation and Mitigation Strategies program for LA/ER opioids, which offers voluntary education on risks and risk management associated with opioid use that is funded by manufacturers, will be updated to reflect the new labeling.

The FDA is not alone among regulatory agencies and medical organizations in publishing policy and regulation changes regarding the use of opioid medications. Other organizations such as the Centers for Disease Control (CDC), the Office of National Drug Control Policy (ONDCP), the Federation of State Medical Boards, the American Society for Interventional Pain Physicians (ASIPP), the American Pain Society (APS) and the American Academy of Pain Medicine have recently published new or updated previous versions of guidelines in response to reports of increases in opioid-related deaths with concomitant increases in the rate of opioid prescribing.^22,23,24

FEDERATION OF STATE MEDICAL BOARDS:

REVISED MODEL POLICY FOR THE USE OF OPIOID ANALGESICS IN THE TREATMENT OF CHRONIC PAIN

The Model Policy for the Use of Opioid Analgesics in the Treatment of Chronic Pain, published by the Federation of State Medical Boards (FSMB), was revised in August 2013.²⁵ The policy assists state medical boards in advising and regulating physicians with regard to medically appropriate prescribing practices when using opioid medications for the treatment of chronic pain. It was updated to address dramatic increases in rates of abuse, misuse, and diversion of opioid medications with increased morbidity and mortality in the United States.²² The updated policy emphasizes the need to assess and treat chronic pain as well as promote access to substance abuse and addiction treatment for high-risk patients. It recommends that physicians screen patients for history of abuse, misuse, or opioid addiction prior to and subsequent to prescribing opioid medications.

The 2013 FSMB revised model policy describes expectations for prescribing of opioids and stresses areas where opioid prescribing would be departures from accepted best clinical practices:

• Inadequate assessment to determine that opioids are clinically indicated.

• Inadequate determination of risks associated with opioid use.

• Inadequate monitoring of outcomes during the use of potentially abusable medications.

• Inadequate education of patients.

• Failure to obtain substantive informed consent.

• Escalation of dose without adequate attention to risks or alternative treatments.

• Excessive reliance on opioids, particularly high-dose opioids, for chronic pain management.

• Failure to make use of available tools for risk mitigation.

The revised FSMB model policy emphasizes that competent physicians must be capable of managing patients with chronic pain with appropriate assistance from specialists when necessary. Although opioid medications may be used to provide pain relief, the use of such medications for purposes other than prescribed puts the patient, physician, and society at risk for harm. The policy indicates that physicians are responsible for minimizing risks of abuse and diversion of prescription opioids by prescribing to carefully selected patients only for whom opioid therapies will provide benefit and by reevaluating periodically the benefits versus the risks of their continued use.

Although it is intended to support the work of state medical boards, the FSMB model policy can be a tool to educate physicians in appropriate use of opioid medications as part of a comprehensive chronic pain treatment plan for their patients. The model policy is not intended for use as a rigid algorithm from which deviation will be penalized by state medical boards. However, deviations from the general recommendations contained within the model policy should be supported with documentation of sound medical justification. Additionally, it is expected that assessment of the benefits versus risks of the treatment plan for a specific patient be recorded in the medical record.

The FSMB model policy is divided into the following categories:

• Patient evaluation and selection.

• Development and documentation of a treatment plan.

• Informed patient consent, agreement, and initiation of treatment.

• Periodic review of the treatment plan and monitoring.

• Consultation and referral.

• Discontinuation of opioid therapy.

• Maintenance of the medical record.

FSMB MODEL POLICY: PATIENT EVALUATION AND SELECTION

Accurate assessment, diagnosis of pain generators, and effective treatment of pain are essential for the patient with chronic pain. Evaluation is key to identification of patients with chronic pain who may need and benefit from opioid therapy for pain. An in-depth evaluation will explore the risks and benefits of a proposed therapy, including treatment with opioid medications. Such an evaluation should include a medical history and systems review, physical examination, review of pertinent imaging studies, and review of laboratory results as dictated by symptomatology and patient history.

The physician should assess the nature and intensity of pain and the effect that pain has on the patient's daily life (functional impact). Issues such as sleep, mood, relationships, and ability to participate in recreational activities should be reviewed and documented. Validated brief assessment tools such as the three-question “Pain, Enjoyment and General Activity Score” (PEG)²⁶ may be helpful in determining the global effect of chronic pain on a patient's life. Particular attention should be paid to evidence of untreated preexisting or onset of mental health illness, such as depression. This is important because patients with mental health comorbidities are at increased risk for abuse, misuse, and overdose of controlled medications.

As use of prescription opioid medications for illicit purposes such as recreation, diversion, or related to chemical dependency is higher than previously thought, the FSMB model policy emphasizes that opioid prescribers must protect the patient and the community at large from harm related to opioid misuse or abuse. Patients may not be forthright about their motivations for seeking opioid therapies for pain relief for various reasons. A detailed history of present and past alcohol, illicit and prescription drug abuse as well as history of physical, emotional, and sexual abuse should be obtained. Such information can be helpful, though not conclusive, to identify a particular patient's risk for misuse of opioid-based medications and chemical dependency. It may be helpful to corroborate a patient's health and behavior history with close friends or family members. Screening tools such as the Screener and Opioid Assessment for Patients with Pain (SOAPP-R)²⁷ and the Opioid Risk Tool (ORT)²⁸ can assist the physician in assessing a patient's potential risk for opioid misuse. The use of prescription drug monitoring programs (PDMPs) and confirmatory tests such as urine drug screening are also expected to be useful when available.

The treatment of a patient with both chronic pain and chemical dependency issues presents a unique challenge. It is now advised that patients who have an active substance abuse disorder, with the exception of tobacco, should be considered unsuitable candidates for opioid therapy until they have enrolled in, and preferably completed, a substance abuse treatment program.²⁹ Other non-opioid therapies, however, should be pursued as viable options.

FSMB MODEL POLICY: DEVELOPMENT AND DOCUMENTATION OF A TREATMENT PLAN

The FSMB model policy emphasizes early and ongoing treatment planning centered on reasonable and objectively demonstrable goals. Treatment goals include attainable function, improvement in symptoms such as sleep disturbance, and the avoidance of unnecessary medication use. Particular attention should be paid to mental health goals such as reduction in anxiety and depression as these are often associated with chronic pain. The patient should be counseled that opioid medications are not considered the primary treatment for any of the above-mentioned treatment goals. In some patients, judicious use of opioid medications may supplement pharmacologic and nonpharmacologic therapies as part of a comprehensive treatment plan. The efficacy of a treatment plan is enhanced by the incorporation of a multidisciplinary team approach; however, referrals and consultations to appropriate specialists should also be included. In order to evaluate progress, the treatment plan, as well as appropriate goals, should be documented and reviewed frequently. To accommodate changes in the patient's overall health and pain-generating conditions, prescribers are encouraged to review the full breadth of employed and available therapeutic modalities as well as the objectives of treatment.

FSMB MODEL POLICY: INFORMED PATIENT CONSENT, TREATMENT AGREEMENT, AND INITIATION OF TREATMENT

The FSMB model policy states that patients must be informed of the benefits and risks of treatment for a medical condition, which is most important for opioid-based therapies. When a trial of opioid medications for treatment of chronic pain is agreed upon, it is recommended that an agreement outlining the elements of informed consent and treatment conditions be written. The document is sometimes referred to as a “treatment contract.” The agreement should be signed by the prescribing physician, the patient, or the patient's legal guardian and ideally the patient's primary care physician if another provider is prescribing opioid medications. The treatment contract formally documents the shared decision between the patient and treating physician(s) that, after careful consideration of the risks and benefits, a trial of opioids will be administered. The treatment contract also documents informed consent and specifics of the treatment agreement.

The informed consent portion of the treatment contract outlines the following patient education points:

• Risks and anticipated benefits of chronic opioid therapy.

• Potential short-term and long-term adverse events such as

• constipation and cognitive dysfunction.

• Likelihood of tolerance and physical dependence.

• Risks of drug interactions, oversedation, and potential respiratory arrest.

• Risk of impaired motor skills, including the ability to drive safely.

• Risk of opioid misuse, dependence, addiction, and overdose

• Limited evidence regarding the benefit of long-term opioid therapy.

• Prescribing policies and expectations, including the number and frequency of prescription refills, as well as the physician's policy on early refills and replacement of lost or stolen medications.

• Specific reasons for which drug therapy may be changed or discontinued (including violation of the policies and agreements written in the treatment contract).

The treatment contract documents the following joint responsibilities of the treating physician(s) and patient:

• Goals of treatment in terms of pain management, restoration of function, and patient safety.

• Patient's responsibility for safe medication use, such as not using more medication than prescribed or using opioid medications in combination with alcohol, storing medications in a secure location, and safe disposal of any unused medication.

• Patient's responsibility to obtain prescribed opioids from single physician or practice.

• Patient's agreement to periodic confirmatory drug testing.

• Physician's responsibility to be available to care for unforeseen problems and prescribe scheduled refills.

After a decision is made that benefits of treatment outweigh risks, and all appropriate screening, workup, and informed consent/treatment contract are completed, opioid medications should be tested for a trial period, usually no longer than 90 days. To minimize risk, the lowest dose of a short-acting medication should be used in the early phase, especially for opioid-naïve patients. Doses can be carefully titrated to effect and, if desirable, may be converted to long-acting preparations while incorporating nonpharmacologic modalities to minimize dose escalations. Regular evaluations should be performed throughout the trial period to assess the progress in achieving treatment goals and to determine the beneficial and harmful effects of opioids on the patient's pain experience, function, and quality of life. The decision to continue therapy beyond the trial period should be made after careful evaluation of the progress in achieving treatment goals and any risks or adverse events during the trial period.

FSMB MODEL POLICY: PERIODIC REVIEW OF THE TREATMENT PLAN AND MONITORING

It is important to regularly evaluate and adapt the treatment plan based on individual circumstances and any changes in risk or adverse events. Physician should regularly review the patient's health record, obtain collateral information from family members or close friends, and review the state PDMP. Gathering information from as many sources as possible will aid in determining the patient's response to the overall treatment plan, including opioid medications. Evaluations should be most frequent at the initiation of treatment as dose adjustments and modifications to the treatment plan may need to be made. However, ongoing vigilant follow-up is expected throughout the course of treatment and arrangements must be made for patients to obtain follow-up, review of outcomes, and a reasonable process for refills of medication.

The decision to continue, modify, or eliminate opioid medications from the treatment plan should be based on assessment of the patient's progress toward treatment goals and satisfactory responses to treatment, as well as evidence of adverse events, including diversion, overdose, or other misuse. Evidence of satisfactory response to treatment is indicated by reduced pain, increased function, and reports from the patient, caregivers, or other collateral sources regarding overall increased quality of life. One way to assess these variables is the “5As” of chronic pain management,³⁰ which should be assessed at each follow-up visit:

• Analgesia. Determination of whether the patient is experiencing a reduction in pain

• Activity. Demonstrated improvement in level of function

• Adverse effects. Negative side effects caused by medication

• Aberrant behaviors. Substance-related behavior and compliance with the treatment plan

• Affect. Mood of the individual

Patient or caregiver reports and observation of patient behavior in follow-up visits may be adequate to detect some problems with compliance but not others. Periodic pill counts and consultation with the state PDMP can be useful in monitoring adherence to the therapeutic plan. PDMPs can be invaluable for identifying patients who have multiple prescribing episodes (“doctor shopping”) related to controlled substances.

Periodic drug testing is an important monitoring tool to detect the use of prescribed and nonprescribed or illicit drugs. Frequency of drug testing is determined by the clinical judgment of the treating physician. However, drug testing is imperative for patients if concerns for addiction, abuse, or diversion are heightened and should be performed as frequently as necessary to support risk management. Although there are many methods of drug testing available, urine drug screen testing is convenient and cost effective.³¹ The testing performed for monitoring chronic pain patients does not usually follow forensic standards for collection, such as observed collection of the sample or following chain-of-custody protocols, but is still helpful in monitoring adherence to an agreed treatment plan. Point of care (POC) immunoassay testing often provides only identification of drug classes. Follow-up confirmatory testing, such as gas chromatography/mass spectroscopy (GC-MS), is often necessary for identification of specific drugs. When ordering confirmatory drug testing, it is useful to document the prescription medications that the patient should be taking as this will assist in a more accurate interpretation of the results by the laboratory.

Aberrant test results should be discussed with the patient in a positive and supportive manner. Regardless of the changes made regarding the continued use of opioid medications to treat chronic pain, the physician should reassure the patient that he or she will be treated with the best and safest care. A supportive physician-patient relationship can facilitate positive behavioral changes in the patient. Test results and details of subsequent discussion with the patient should be documented in the medical record.

Physicians who prescribe opioid therapies should be experienced in the identification of substance abuse and physical dependence and the diagnosis of substance abuse disorders. Patient behaviors such as recurring misuse, unauthorized dose increases, deteriorating function, evidence of forged prescriptions, and documented diversion are particularly worrisome and require immediate intervention by the physician. Failure to act can place the patient at risk for harm from accidental overdose, injury to self or others, arrest, incarceration, and even death.

FSMB MODEL POLICY: CONSULTATION AND REFERRAL

Treatment of patients with chronic pain can be complex with many challenges. Consultation with others who have greater knowledge and specialization related to the needs of a patient (i.e., psychiatry, neurology, PM&R, pain management, addiction medicine, physical therapy, psychology, social work) is an expected component of safe chronic pain management. Consultation with specialists may be needed for patients with comorbidities such as mental health disorders, addiction, and physical deconditioning.

FSMB MODEL POLICY: DISCONTINUATION OF OPIOID THERAPY

The FSMB model policy emphasizes that decrease or discontinuation of opioid therapy is a treatment option, which is especially true if continued use of opioid medications poses greater risk than benefit. Recent studies suggest that when opioids are significantly reduced or stopped, some chronic pain sufferers do no worse in terms of reported pain and function, whereas others may even improve.^1,32 Reasons for discontinuation of opioid therapy include resolution of pain, intolerable adverse effects, inadequate analgesia or hyperalgesia, deteriorating function, and evidence of medication abuse, misuse, or diversion.

Patients who have used opioids for more than a short time should be expected to have some degree of physical dependence. Tapering or discontinuing opioids in such patients may require slow downward titration and the assistance of an addiction specialist. It should be emphasized that the decision to discontinue opioid medications does not constitute a discontinuation of pain treatment. Use of opioid medications should be one component of a multimodal treatment plan. Other non-opioid modalities should continue to be viable options.

FSMB MODEL POLICY: MAINTENANCE OF MEDICAL RECORDS

Physicians should maintain medical records documenting treatment plans as they treat a medical condition. Documentation is most important when prescribing opioid medications to treat patients for chronic pain. The medical record should reflect the medical decisions that led to choosing opioids (risks vs benefits), the risk assessment, and the risk management plan. Documentation includes all orders for medications, especially opioid medications and other controlled substances. Documentation of instructions given to the patient regarding appropriate medication use (e.g. timing of doses, indications for taking medication for break through pain, avoidance of alcohol while using opioid medications, etc.) should also be written in the medical record. The name, address, and telephone number of the patient's pharmacy should also be recorded for easy reference in case questions arise.

The following elements are to be included in the medical record:

• Instructions to the patient and others caring for the patient, which include discussions of risks and benefits of opioid therapy.

  • A copy of signed treatment agreements or consents should be included.

• Documentation of patient progress (or lack of progress) in terms of pain management and functional improvement.

• Notes regarding evaluations and consultations with specialists.

• Information used to support the initiation, continuation, revision, or termination of opioid-based treatment and the steps taken in response to any aberrant medication use behaviors.

  • These may include medical records, notes from past hospitalizations, and treatments by other providers.

• Authorization for release of information to other treatment providers.

All records should be ready for immediate review if necessary. If a desired outcome is not achieved, complete documentation of the treatment plan and follow-up is needed to protect the physician and patient.

CENTERS FOR DISEASE CONTROL: GUIDANCE FOR OPIOID PRESCRIBING

Data released by the Centers for Disease Control and Prevention (CDC) show that the number of opioid-related poisonings doubled between 2001 and 2011²³ and opioid prescriptions quadrupled over the same time period.^23,24 The CDC had previously offered guidance for opioid prescribing to health care providers (HCPs) based on expert opinion:³³

• Use opioid medications for acute or chronic pain only after determining that alternative therapies do not deliver adequate pain relief. The lowest effective dose of opioids should be used.

• In addition to behavioral screening and use of patient contracts, consider random, periodic, targeted urine testing for opioids and other drugs for any patient younger than 65 years old with noncancer pain who is being treated with opioids for more than 6 weeks.

• If a patient's dosage has increased to greater than 120 morphine milligram equivalents per day without substantial improvement in pain and function, request consultation with a pain specialist.

• Do not prescribe long-acting or controlled-release opioids (e.g., OxyContin, fentanyl patches, and methadone) for acute pain.

• Periodically request a report from your state prescription drug monitoring program

SUBSTANCE ABUSE AND MENTAL HEALTH SERVICES ADMINISTRATION: OPIOID SAFETY TOOLKITS

Data that clarify the substantial risks associated with prescription opioid use have prompted the Substance Abuse and Mental Health Services Administration (SAMHSA) to publish a collection of opioid safety toolkits.³⁴ Individual toolkits target prescribers, patients, first responders, general community members, and opioid overdose survivors and their families. Each SAMSHA toolkit addresses topics pertinent to a target audience such as signs and symptoms of acute opioid overdose, proper storage of medications, utilization of Prescription Drug Monitoring Programs (PDMPs), and other methods to reduce harm associated with the misuse of prescription opioid medications. The toolkits offer several strategies for minimizing the risk of unintended overdose death related to prescription opioids:

• STRATEGY 1. Encourage providers, persons at high risk, family members, and others to learn methods to prevent and manage opioid overdose (OD).

• STRATEGY 2. Ensure access to treatment for individuals misusing or addicted to opioids or with other substance use disorders.

• STRATEGY 3. Ensure ready access to naloxone.

• STRATEGY 4. Encourage the public to call 911.

• STRATEGY 5. Encourage prescribers to use state Prescription Drug Monitoring Programs (PDMPs).

The SAMHSA toolkits provide specific instructions for HCPs for administration of naloxone to treat acute opioid overdose. Specific instructions regarding naloxone coincide with increased support from certain states that are taking steps to allow HCPs to make naloxone available to a person at risk of an opioid-related overdose or a family member, friend, or other person in a position to assist a person at risk of an opioid-related overdose.³⁵

Individuals with the greatest need for prescribing naloxone along with opioids include individuals who are:

• Taking high doses of opioids for long-term management of chronic malignant or nonmalignant pain.

• Receiving rotating opioid medication regimens and are thus at risk for incomplete cross-tolerance.

• Discharged from an emergency department following opioid intoxication or poisoning.

• At high risk for overdose because of a legitimate medical need for analgesia, coupled with a suspected or confirmed history of substance abuse, dependence, or nonmedical use of prescription or illicit opioids.

• Completing mandatory opioid detoxification or abstinence programs.

• Recently released from incarceration and a past user or abuser of opioids (and presumably with reduced opioid tolerance and high risk of relapse to opioid use).

The SAMHSA tool kits go further in recommending that at the time of prescribing, clinicians should inform their patients that it is illegal to sell, give away, or otherwise share medication with others, including family members. The clinician's role as a patient educator is highlighted with emphasis placed on explaining patients’ significant obligation to keep their medication in a safe place such as a locked cabinet. Patients must be instructed that access to controlled substances must be restricted and disposal of any unused supply must follow safety guidelines.

For additional information on prescribing opioids for chronic pain, SAMHSA recommends the following websites:

• www.opioidprescribing.com

  Sponsored by the Boston University School of Medicine, with support from SAMHSA

• www.pcss-o.org

  Sponsored by the American Academy of Addiction Psychiatry in collaboration with other specialty societies and with support from SAMHSA

• http://www.medscape.org/viewarticle/770687 and http://www.medscape.org/viewarticle/770440

  Course modules sponsored by NIDA &posted on MedScape.com

RESCHEDULING HYDROCODONE

Hydrocodone is regarded by some physicians as a “safer” opioid medication because of its classification as a schedule III drug rather than schedule II drug as are most other opioid medications. The fact that hydrocodone is combined in formulations containing acetaminophen or aspirin may have led some to believe it has less potential for abuse because of the widely recognized risk of hepatotoxicity and acetaminophen overdose. However, the Drug Enforcement Administration (DEA) has reported that hydrocodone is the second most abused prescription opioid in the US.³⁶

The FDA has announced support for reclassification of hydrocodone-acetaminophen products from schedule III to schedule II.³⁷ Such a reclassification provides recognition that hydrocodone has equivalent or greater risk for misuse compared with other opioid medications. As this is the most prescribed drug in the United States, the reclassification sends a clear message that, regardless of its compounding, hydrocodone prescribing requires the same level of vigilance as any high-risk opioid. In August 2014, hydrocodone was reclassified as a controlled-substance schedule II drug. The FDA has also approved a new single entity, long-acting hydrocodone preparation.³⁸

OTHER LEGAL AND REGULATORY ISSUES

Opioid medications are classified as controlled substances because of their high potential for abuse and are regulated by a complex set of federal and state policies, laws, and regulations. At the federal level, prescribers must have a firm grasp of the laws articulated in the Controlled Substances Act (CSA). Under this act, licensed professionals can prescribe, dispense, and administer controlled substances for legitimate medical purposes. Schedule I drugs such as heroin have no accepted medical use. Most opioid drugs used in medical practice are schedule II medications. Hydrocodone has been rescheduled from schedule III to schedule II.

In 2006, the Drug Enforcement Agency (DEA) released an updated Practitioner's Manual that summarizes and explains the basic requirements for prescribing, administering, and dispensing controlled substances under the CSA (www.deadiversion.usdoj.gov). In the fall of 2007, the DEA issued a final ruling that amends its regulations to allow practitioners to provide individual patients with multiple prescriptions to be filled sequentially for the same Schedule II medication. This ruling allows prescribers to write sequential prescriptions for up to a 90-day supply of a particular controlled substance. These prescriptions must be dated the day the prescriptions are written and would have sequential and nonoverlapping fill dates [one could be for immediate filling]. For example, a prescriber might state “do not fill until 30 days from prescription date” or “do not fill until 60 days from a prescription date” (www.deadiversion.usdoj.gov/fed_regs/rules/2007/fr1119.htm). In 2010, the DEA adopted new rules for allowing prescribers registered with the DEA to prescribe scheduled substances electronically and allow pharmacies to receive, dispense, and archive electronic prescriptions. (www.deadiversion.usdoj.gov/ecomm/e_rx/).

CONCLUSION

As the number of patients seeking medical care for chronic pain increases, demand for safe and effective pain management will increase. Prescribers must remain aware of new medication regulations, policies, and sanctioned recommendations by professional medical organizations in order to make informed decisions about best practices for opioid prescribing to protect their patients and the members of the communities they serve.

Pain is one of the most common reasons a patient will seek medical help. However, treating a patient with chronic pain can be a difficult challenge. The use of opioid medications in the treatment of chronic, noncancer pain is controversial because of the increase in prescription drug abuse. Initiating and continuing opioid therapy is a serious endeavor that requires complex medical decision making and substantial risk management. Prescribers who hold to the risk and benefit analysis will find that the evidence of benefit of chronic opioid prescribing for chronic pain is weak and the evidence for risk is clear, significant, and mounting.

Current professional guidelines for prescribing opioids are increasingly detailed and prescriptive as to their requirements for risk management and sound and shared medical decision-making. They provide a basic framework by which clinicians and regulatory boards can determine that a particular practice is within the current standard of care. The guidelines require an informed and engaged clinician and patient, with each able to initially and continually assess the risks and benefits of various treatment modalities. Clinicians must continually seek updated information regarding advances in research and drug development as well as changes in state or federal regulations while maintaining adequate vigilance for potential opioid misuse by patients. The guidance from regulatory groups such as the FDA, FSMB, and SAMHSA enables clinicians to formulate a treatment plan for patients with chronic pain that reduces reliance on opioids.

REFERENCES

INTRODUCTION

With the passage of the Harrison Narcotics Tax Act in 1914, the United States federal government put states, as well as physicians, nurses, and patients, on notice that treatment of those with “narcotic addiction” with drugs, specifically opiates and cocaine, was outside the purview of medical practice and was henceforth illegal.¹ Those who championed the Harrison Act saw a distinction between those with addiction and those with pain and saw the law as necessary to halt what many in the United States saw as a headlong slide into producing generations of opioid, cocaine, and marijuana addicts. Several years later, a political coalition of many of the same advocates saw the Volstead Act ratified as a Constitutional amendment banning the use of alcohol for recreational purposes. That “Great Experiment” lasted barely 13 years; drug prohibition, however, has continued.²

It was not until 60 years later with the adoption of the Narcotic Addict Treatment Act of 1974 that physicians could prescribe opioids to those with opioid addiction, but only in the context of federal and state licensed methadone treatment programs. In the interim 60 years, the use of prescribed opioids to treat pain was generally limited to acute pain of injury or surgery and in patients with chronic pain related to cancer and other terminal conditions. Even for these latter groups, great concern was expressed about the addictive nature of these medications, and such drugs were used sparingly.

In the last four decades, however, there has been a growing movement to extend pain treatment, particularly with opioids (as well as sedatives/benzodiazepines and other potentially dependency-producing medications) to those with nonterminal painful conditions.^3,4 In the last 10 years, the prescribing of opioids has increased fourfold, with a similar increase in overdose deaths, with grave concerns among the public, government officials, and the medical profession about these trends. A growth industry of pain clinics, many of which were no more than for-profit opioid and benzodiazepine dispensaries, has prompted some law enforcement and regulatory action, with calls for more.^5-7

Original concerns expressed about the increasing availability of opioids for pain treatment were muted by assertions from experts that the prevalence of addiction in those who were treated for pain was astonishingly low.⁴ Portenoy et al. asserted that undertreatment of pain and specifically “opiophobia” were greater concerns than overprescribing.^3,8 The Joint Commission on Accreditation of Health Care Organizations (JCAHO) declared pain as “the fifth vital sign” and judged hospitals by how well they addressed it.⁹ However, in recent years, many experts have expressed concerns and admitted that overprescription and misuse, as well as outright abuse, have become significant problems, with associated mortality and morbidity^5-7 They advocate specially trained physicians to prescribe opioids in long-term nonmalignant pain,^10-11 and/or to develop risk evaluation and mitigation strategies for opioid prescribers.^12-14

As a physician specializing in the treatment of patients with chemical dependency (CD), the author has developed some expertise in pain management and has treated a number of patients with both addiction and pain. A number of pain physicians may feel the need to recognize and assist in the management of CD in their patients, and some have become experts in this field as well. Many of our colleagues in CD treatment, including anesthesiologists, psychiatrists, internists, family physicians, and others, are now active in both treatment and research in this area.

A new interface in CD and addiction treatment came with the approval of buprenorphine alone (Subutex and generics) and with naloxone (Suboxone^®, Zubsolv^®, BunavailR and generics). Although buprenorphine is not approved for the treatment of pain except for the preparation for injection; however, for patients with the combination of pain and actual or potential opioid addiction, it has proved helpful in the management of both problems.^15,16

This chapter will: 1) describe the diagnostic criteria for CD; 2) assist those who treat pain to set up practices which will discourage and perhaps eliminate those “drug-seekers” who attempt to obtain medications solely for diversion and profit; 3) educate pain physicians about appropriate screening measures to detect those who are chemically dependent or at high risk of developing CD; 4) discuss methods to detect the development of aberrant behaviors associated with addiction; 5) present the importance of appropriate referral for CD treatment, including the importance of determining that referral sources are expert in the appropriate management of these patients; and 6) describe potential tools available to pain physicians that will assist in the management of patients with CD.

IDENTIFICATION OF CHEMICAL DEPENDENCY

The Diagnostic and Statistical Manual of the American Psychiatric Association, 5th edition (DSM-5), is the American standard for the diagnosis of CD.¹⁷ The DSM-5 shows particular concern regarding the differentiation of physical dependency, which occurs in virtually all patients who regularly take drugs that produce receptor dysregulation, from substance use disorders (SUDs), including abuse and dependency. The differentiation between abuse and dependency may be changed in the new edition, perhaps with the use, once more, of the term “addiction.”¹⁸

It is important to emphasize that the amount of drug used and frequency of use are not the dominant issues in CD; it is rather the effects of the drug use on the individual and society, in a persistent and consistent manner, and the inability of these individuals to change their maladaptive behaviors. Of course, as drug use escalates and becomes more frequent, one commonly sees these behavioral issues, and ultimately pathological physical and mental changes. However, there are individuals who may use larger amounts of a particular drug without ill effects, while others who use smaller amounts, perhaps even less frequently, still develop serious problems with its use.

DSM-5 eliminates the sometimes confusing distinction between the “Dependency” and “Abuse” categories, replacing them with a unitary “Substance Use Disorder” category for each class of drugs, where the criteria are put together into the 11 existing criteria, with the replacement of recurrent legal problems with the criterion of “drug craving.” The specifiers are “absent” for 0 to 1 criterion, “mild” for a total of 2 to 3 criteria, “moderate” for 4 to 5 criteria, and “severe” for 6 or more criteria.¹⁶ The moderate to severe category may become synonymous with “addiction.” The presence of only tolerance and withdrawal in a patient taking appropriately prescribed medications in an adherent manner will not result in a SUD diagnosis.¹⁸

The use of screening instruments, such as the screener and opioid assessment for patients with pain (SOAPP), is discussed elsewhere (Chapter 19), and tables of “aberrant behaviors” often divided into “yellow flags” and “red flags” (Table 70-1) are based on criteria that are enunciated in the DSM criteria for CD. The diagnosis of CD, however, should not be based on screening tools but on application of the DSM-5 criteria. However, the pain physician must be aware that many of the behaviors associated with addiction can also be present in pain patients (so-called “pseudo-addiction”), particularly in those who have been previously undertreated with opioids, as well as those who have had adverse experience with opioid tapers.^19,20 These behaviors may include drug hoarding, doctor shopping, lack of adherence to dosing schedules, and others.

THE “DRUG-SEEKING” PATIENT

This term “drug-seeking” patient has become so widely and inappropriately used as to become meaningless. All pain patients are concerned with relief of their pain, and often that relief involves a number of drugs; some patients are inordinately fixated on obtaining those medications. However, the term “drug-seeking” refers here to individuals who are not patients, do not have pain problems, and who attempt to obtain opioids and other controlled substances solely for the purpose of abusing the drugs for euphoria and/or diverting them for profit. Individuals who are solely diverting and selling these drugs are criminals and can and should be referred to appropriate authorities.

Drug-seeking patients who attempt to obtain opioids from physicians solely with the intent of abusing them for euphoria, however, are very likely to be CD. In some cases, patients may be obtaining medications and selling them to obtain their drug of choice. Although these activities are illegal, efforts to direct these patients to CD treatment should be encouraged. Unlike the former group of diverting individuals, patients, if successfully treated, are far less likely to reoffend. Drug courts that specialize in drug-related nonviolent crime may be very useful in motivating patients into treatment, with a very high rate of successful completion.

It is recommended that the pain physician has a “no prescription” policy on a patient's first appointment. The referring physician and/or patient calling for appointment who is self-referred is informed that, if the patient is on controlled substances, those prescriptions must cover the patient through the evaluation process and that the pain physician will not write such prescriptions except under emergency circumstances, if at all. Unfortunately this is not always possible, but a clear statement of such a policy and its emphasis found in telephone directories and websites may discourage pure “drug-seekers” from seeking their drugs at your practice.

Physicians should be alert to the creative ways that patients create “emergencies,” for example, stating that they are visiting from out of town, or calling late on Friday afternoons or weekends, calling only when on-call physicians are available, and many other techniques. Physicians and their staffs should not be persuaded by these urgent requests and insist on a proper intake process, including contact with prior prescribers. If such patients are referred to emergency facilities, a clinical member of the staff should contact the emergency department and speak to the triage nurse or physician regarding concerns.

An interesting study looked at the number of lifetime aberrant behaviors manifested by patients in pain treatment programs and found that the total of aberrant behaviors was a better predictor than the specifics of each aberrant behavior. Patients who manifested four or more aberrant lifetime behaviors were highly likely to have an underlying SUD and have current illicit drug use, whereas those with three or fewer lifetime aberrant behaviors were extremely unlikely to have SUD and current drug use (9.9% vs 1.1%). A positive urine cocaine toxicology test was associated with a fourteenfold increased rate of a SUD.²¹

Pain programs should also utilize state prescription monitoring programs (PMPs) in states where they exist, and physicians should work with colleagues to encourage other states to create them and have them available only to the medical profession (some have only been available to law enforcement and not to physicians, but most are now available to both). PMPs are web-based programs that allow appropriately credentialed individuals to review the prescription records for controlled substances of both new and current patients and can determine whether they are receiving additional prescriptions from other providers, including dates and numbers of pills. This can be enormously helpful in identifying doctor-shoppers and drug-seekers.

Drug testing is also appropriate at the first visit. Toxicology monitoring is dealt with elsewhere in this text (Chapter 19). However, urine or salivary screens, with confirmation of results by more advanced methods, are used to provide confirmation of patients’ statements about what they are being prescribed to look for nonconcordance with toxicology results. In patients on certain drugs (e.g., methadone, fentanyl, oxycodone), assays for the measurement of serum concentrations of the drugs are commercially available and provide information as to whether patients are taking the approximate doses which they state are being prescribed. In some cases, proportions of metabolites may indicate the original drug used by the patient. However, many factors may impact the serum concentrations of these drugs.

PATIENTS WITH CHEMICAL DEPENDENCY AND THOSE “AT-RISK”

Many addiction medicine physicians hold to a “unitary model” of addiction, in which a patient who has developed addiction to any drug, including alcohol, is at high risk of development of addiction to other mood-altering or dependency-prone drugs, whereas others (including the author) believe that there is a spectrum of risk in these patients. At lowest risk of addiction are those with a distant history of CD other than opioids, followed by those who are using mood-altering substances or medications in appropriate and controlled ways. At intermediate risk of addiction are those who actively abuse mood-altering drugs, including tobacco, alcohol, and marijuana, as are those with past histories of opioid abuse. At highest risk of addiction are those who are actively abusing illicit opioids or illicitly obtaining licit opioids.

A. PATIENTS WITH PRIOR CHEMICAL DEPENDENCY HISTORY OF DRUGS OTHER THAN OPIOIDS

Patients with a history of CD, particularly those who have been involved in self-help treatment, particularly 12-step programs, may identify themselves initially as being “in recovery” and express their concerns regarding dependency or addiction on pain medications or anxiolytic agents. Other patients may not identify their addiction or dependency and may go to some lengths to deny a prior history. Denial may be in part because of their shame regarding the stigma of a CD diagnosis and in part because of their fear that pain physicians may not be accepting of their pain history and/or believe that they are drug seeking.

Patients with prior histories of CD may be at higher risk of abuse of opioids and benzodiazepines. Although it is important for all patients to explore maximizing nonpharmacologic treatment as well as non-opioid pharmacotherapy, it is most important for patients with prior history of alcohol, cocaine, and/or other stimulants, cannabis, or other CD. Again, many patients will urge doing so. Some patients will resist starting opioids or benzodiazepines even when clearly indicated.

The pain physician, when working with a patient in recovery, should review the patient's support system. If the patient is not involved in active counseling or a self-help group (including a sponsor and a “home” group), the physician should urge the patient to increase the level of support. If the patient's family system is intact, involving and educating the significant other(s) to the risks of opioid or benzodiazepine abuse may be of benefit. Although informed consent of all patients involves a frank discussion or risks/benefits, particularly those of physical dependency and addiction, this discussion is important in the patient with prior CD history.

In a patient with prior alcohol abuse, the pain physician should consider following the patient not only with usual toxicology studies but also with existing biomarkers for alcohol abuse, including a baseline CBC (with MCV), uric acid, triglycerides, ALT/AST, and γ-glutamyl transpeptidase (GGT). Newer biomarkers, commercially available, include carbohydrate-deficient transferrin (CDT), a reliable indicator of recent heavy alcohol consumption even if the individual has been abstinent for several days before the test. A test, which can be obtained together with a urine toxicology test, is the measurement of ethyl glucuronide (EtG), which can detect alcohol consumption for up to 48 hours prior to testing; ethyl sulfide (EtS) is complementary test and may be used instead of or in addition to EtG, with a slightly longer period of detection.²²

It has been the author's practice to recommend that the patient who is actively involved in a 12-step program inform his or her sponsor or obtain a sponsor if one is needed and have the sponsor be actively involved in the patient's care. For patients in another support system (e.g., SMART Recovery, LifeRing, Women for Sobriety, and others), a more senior treatment “colleague” or the facilitator of their group may be similarly helpful.²³ For patients not so involved, discussion of the risks of relapse should include strong recommendation for developing a professional therapeutic relationship, either individual or group with a CD support group or with a pain support system. Some addiction programs have developed combination pain/addiction support groups.

Pain practices vary in their approaches to “social” drinking in patients receiving opioids. In patients with a prior history of alcohol abuse, any “social” use is significant and indicates relapse, with the likelihood of heavier drinking in the future. Many programs recommend total abstinence because of potential synergistic effects of alcohol with opioids and benzodiazepines, as well as drug-drug interactions secondary to alcohol effects on P-450 cytochrome enzymes. However, few programs routinely inquire about alcohol use at each visit; fewer still do any testing for alcohol metabolites or effects. Use of urinary EtG and/or EtS tests may indicate alcohol consumption within the 1 to 3 days prior to testing, which may be useful if the levels are high or if the patient has not given a history of alcohol use. Low levels of EtG and EtS may, however, occur with exposure to mouthwashes, alcohol in medications or foods, or even inhaling the vapors of alcohol-based skin sanitizers, which are over 60% ethyl alcohol.

Patients with prior histories of abuse of other drugs, particularly cocaine and amphetamines, as well as men younger than 35 years of age, are at higher risk of developing addiction to opioids. Treatment agreements clearly state that use of nonprescribed controlled substances or illicit substances will result in potential detoxification or immediate discharge; therefore, follow-up of those with prior histories should include ongoing toxicology studies, perhaps on a more frequent basis, including random call-backs (often with a 24-hour window) for toxicology studies, sometimes with pill counts.

A particularly difficult and controversial area involves patients who are using forms of cannabis, including marijuana and hashish. Many states have “medical marijuana” laws that permit patients to receive a “prescription” from medical professionals to allow them this use without state or local authorities charging them with criminal offenses. In some states, marijuana “dispensaries” are licensed where patients with medical marijuana cards can purchase it legally. However, others (particularly in states without dispensaries) obtain marijuana through the illegal sales systems.

Many pain physicians are concerned that patients who are using marijuana “medically” are still engaging in illegal activity by purchasing it, as well as having contact with other illicit drugs which may be sold by the same individuals. Others are concerned about the violation of federal laws by such patients. Still others have concerns about the potential for drug-drug interactions. Finally, many programs are concerned about DEA surveillance and prescribing controlled substances to those who are using cannabis or any illicit drug.^24,25 Some patients have prescriptions for medical dronabinol (Marinol), which makes determining the origin of positive THC urine drug screens problematic. Prescribing for opioids and other controlled substances for those using cannabis products remains a judgment call for each health professional.

B. PATIENTS ACTIVELY ENGAGED IN SUBSTANCE ABUSE

Patients who actively engage in substance abuse, whether with alcohol or with other substances, may present with serious painful conditions either from the underlying disorder (e.g., chronic pancreatitis, neuropathy from medications used to treat HIV) or from the causes of chronic pain. Some patients may be functional when abusing drugs and alcohol, and detection may be difficult. Standard screening instruments (e.g., AUDIT, MAST, DAST) may be helpful in some patients,²⁶ as well as screening tools developed to look for those at risk of abusing medications prescribed for pain, such as the SOAPP-R.²⁷ Pain physicians, specifically those in general medical practices who treat pain in their patients, may continue to treat patients who are known to be abusing other substances, depending on the severity of the abuse and drug(s) involved. However, these physicians do not use controlled substances in their treatment and focus on nonpharmacologic treatment and non-opioid pharmacologic treatment, as well as avoiding benzodiazepines and other sedatives.

In most cases, it is appropriate to refer such individuals to a treatment facility for CD. In those who are without physical dependency or withdrawal risks and who do not need a higher level of care, outpatient treatment may be appropriate. For those with more significant CD, referral to either free-standing or hospital-based detoxification facilities may be necessary. Upon discharge, there should be consideration for the use of anticraving drugs which are available for alcohol and for other drugs as well. Both detoxification and these agents are further discussed in the section on termination later in the chapter. One option for opioid treatment of pain in at-risk patients for chemical dependency, is the use of buprenorphine. While this can be done in the form of transdermal preparations approved for the treatment of pain, the use of buprenorphine or buprenorphine/naloxone sublingual preparations can also be considered off-label (Heit, H. DEA letter, personal communication, 2004). There may be insurance or pharmacy issues with such off-label prescribing.

C. PATIENTS WITH PRIOR HISTORY OF OPIOID ABUSE

The American Pain Society (APS), the American Academy of Pain Medicine, and the American Society of Addiction Medicine issued a joint policy statement in 2004, asserting that although physicians knowingly giving opioids to patients at high risk of diversion and/or abuse without medical necessity is inappropriate, it is equally problematic to deny appropriate treatment to patients with past or current histories of opioid abuse.²⁸ Of course, appropriate evaluation as well as careful monitoring is necessary in these patients.

As with patients with histories of other types of CD, every effort should again be made to maximize the use of nonpharmacologic therapies, as well as non-opioid drug therapy. The pain physician should inquire as to the patient's support system, and as with others with CD, every effort should be made to have the patient in appropriate treatment. For those already in a program, whether formal or informal (e.g., 12-step programs, SMART Recovery), recommendations to obtain and involve a sponsor and/or therapist, as well as appropriate family and friends, may be helpful in providing support during what will likely be an increased likelihood for craving and relapse. If the patient feels he or she is not in need of treatment, the physician may consider requiring the patient entering and remaining in treatment as part of the initial treatment agreement, or it may be presented initially as a contingency at the first sign of aberrant behaviors.

In patients with a prior opioid abuse history, it may be advisable to avoid use of the primary drug that the patient abused, particularly forms of oxycodone, as they have little hepatic first pass, can easily be used by nasal insufflations, and cross the blood-brain barrier rapidly, producing more euphoria. The patient's drug(s) of choice may also be triggers, further increasing the chance of abuse. The use of slow-acting agents such as continuous-release (CR) morphine or transdermal fentanyl should be considered when long-acting drugs are needed. Similarly, use of drugs with slower blood-brain barrier passage for acute or breakthrough pain, such as immediate release (IR) morphine, should be considered if such agents are required. Methadone can be legally prescribed for pain, and buprenorphine (an off-label use except for the injectable and transdermal forms) may be an option and is discussed in more detail later in the chapter.

D. PATIENTS WITH ACTIVE USE OF ILLICIT OPIOIDS

Chronic treatment of patients who are actively abusing opioids or other dependency-prone medications, is rarely, if ever appropriate. In the presence of moderate to severe acute pain, administering or dispensing an opioid for relief may be appropriate, but long-term prescribing is fraught with hazard. Such patients are likely to take excessive doses at shorter intervals or may divert licit opioids to obtain their drugs of choice. The clinical, ethical, and medical-legal implications make such prescribing dangerous for the patient and prescriber. In cases where patients are found to be actively abusing illicit opioids (or obtaining licit drugs illicitly), as is the case with other dependency-producing drugs, consideration of the level of use and the likelihood of a withdrawal syndrome should require referral to an appropriate detoxification program. Not all programs are equal, and further discussion of this matter can be found in the section on termination later in the chapter.

In cases involving patients who are taking opioids, pain physicians may want to assess them in an opioid-free state to determine the status of their pain. In those patients who are illicitly using “street” opioids (heroin) and those who are inappropriately using prescribed opioids (e.g., multiple prescribers, frequent early refills, obtaining licit drugs from nonmedical sources), referral to a detoxification facility should also be considered. Such determination may be made on the basis of the level of admitted use and/or the appearance of withdrawal signs and symptoms, as well as their severity. Conventional opinion holds that opioid withdrawal, although uncomfortable, rarely if ever has severe morbidity or mortality; however, the author has seen many cases of severe withdrawal resulting in vomiting, aspiration, pneumonia, myocardial infarction, Mallory-Weiss syndrome, and severe dehydration with renal failure. This is particularly true in older or more debilitated patients (HIV disease, hepatitis C). This is further discussed below.

E. PATIENTS ON OPIOID AGONIST THERAPY

A potentially more difficult decision involves the treatment of pain in opioid-dependent patients who are in treatment, particularly those in methadone agonist treatment. Many pain physicians are not aware of the strictures under which methadone maintenance treatment programs (MMTPs) operate. The basic requirement for admission to MMTPs is that the patient be Opioid Dependent by the old DSM-IV standards, which involves more than physical dependence and essentially labels the patient as a “narcotic addict.” There are many other requirements as well, including being able to pay for the treatment, which may range from $4000 to $6000 per year, usually payable by the week. Most private insurance, despite the recent passage of federal mental health/substance abuse parity acts, will not pay for methadone treatment or will pay only for a brief detoxification. In addition, MMTPs are specifically enjoined from using methadone in the primary treatment of pain.

Methadone is given once daily in MMTPs, which is rarely, if ever, adequate for pain treatment. Patients must come daily for dosing until and unless they earn “take-home” privileges, in which they are initially given one take-home dose and then every 60-90 days may earn an additional take-home. Take-home doses require complete adherence to all clinic rules and regulations. Methadone programs may “split” the doses in patients who are hypermetabolizing the drug, such as pregnant women in their second or third trimester or patients on P-450 enzyme-inducing medications; however, there are legal restrictions on doing this, and it must be approved by both state and federal authorities on a case-by-case basis. Therefore, opioid-dependent patients dismissed from pain treatment who are admitted to MMTPs may continue to experience significant pain. In addition, being in a program with those using heroin and other street drugs may be entirely unacceptable to many patients.

The management of such patients represents a challenge to the pain physician, the MMTP, and the patients themselves. Many of these patients have significant real pain but cannot be depended upon to take medication safely and as directed without dose escalation and without the use of other drugs of abuse. Unfortunately, many of these patients, particularly those in treatment for HIV and hepatitis C complications, receive opioids from their other physicians with little or no consultation with the MMTP medical staff. In addition, opioids may be readily available from nonmedical sources or unscrupulous providers in so-called “pill mills.”

The prescription of long-acting opioids in these patients can result in overlapping peak levels of both methadone and the other prescribed opioid, with risks of oversedation, overdose, and death. In addition, the program is often unable to use urine drug screens effectively, because most program budgets do not permit use of gas chromatography/mass spectroscopy (GC-MS) or other confirmatory tests, so that it becomes difficult or impossible to determine if the patient is taking only the prescribed drugs. Use of short-acting, rapidly absorbed opioids for breakthrough pain similarly makes monitoring the patient for illicit use problematic.

There is a certain irony in individuals who are in methadone treatment programs precisely because they have abused street drugs, whether heroin or illicitly obtained prescription drugs, and cannot be trusted to manage their medication who then receive as much as a month's worth of drugs similar or identical to their drugs of choice. In many cases, patients are selling the prescribed drugs in order to obtain their drugs of choice, particularly heroin, cocaine, or methamphetamine.

As stated above, all physicians treating pain in patients with addiction should exhaust all nonpharmacologic and non-opioid drug treatments in the management of chronic pain. If opioids are needed for acute pain, prescribers need to be aware of methadone-induced tolerance, which will likely require a higher dose of opioid. If the prescription is for fixed-dose acetaminophen combinations, the patient may escalate the dose and have potential problems with acetaminophen toxicity, as well as opioid-related issues. Every effort should be made to contact the MMTP and consult with its medical or nursing staff. Prescribers also need to be aware that prescribing mixed agonist-antagonists in these patients may result in both hyperalgesia and withdrawal. The author has seen several cases of this with tramadol and, more recently, tapentadol (Nucynta^®).

Increasing the dose of methadone is rarely an effective means of treating acute pain both because methadone takes 2 to 4 hours to peak and because reaching a steady state of the increased dose will not take place for 4 to 7 days. Treating acute pain in an emergency department or medical office setting is not generally problematic; however, prescriptions of opioid medication for a week or longer is not without significant risk for these patients. The lowest effective dose should be given for the shortest possible time, with reevaluation every 2 to 3 days. The MMTP nurse and/or physician should be notified as soon as possible of such prescription; ideally, consultation with MMTP staff should be considered prior to prescribing.

For subacute and chronic pain, treatment of methadone-maintained patients should involve collaboration with the MMTP medical staff. In cases of socially rehabilitated MMTP patients who have been in treatment for several years and have extended take-home status and particularly in those with severe and potentially life-threatening medical problems, consideration should be given to turning over the opioid prescribing entirely to the pain physician. Intermediate steps, such as providing split doses, may be possible but are again associated with legal restrictions. Lower-risk opioids, such as methadone (in divided doses), CR morphine, and fentanyl transdermal patches (all of which have potential for abuse), may provide replacement for the methadone dose as well as satisfactory analgesia.

Patients who are on either methadone or buprenorphine preparations for treatment of their narcotic addiction present particular challenges in the treatment of significant pain.²⁵ In the case of methadone, tolerance may be very high, and patients may require doses of either other longer-acting opioids or short-acting rapidly absorbed opioids that are many times higher than the usual patients’ doses. In some cases, it is both medically and logistically more logical to include the maintenance dose with the added needed doses for pain together, through the pain physician, either by using methadone as the maintenance pain drug or by converting the methadone dose into the dose of the other drug being used. Such conversions may be difficult, and equivalency tables are notoriously inaccurate, because individual absorption, tolerance, and metabolism play significant roles, often affected by pharmacogenomic differences among patients. “Starting low and going slow,” always an appropriate paradigm, is appropriate for these titrations.

Buprenorphine presents difficulties in addition to tolerance. Unlike methadone, which does not block other opioids—it only increases tolerance to them—buprenorphine has such high receptor affinity and slow receptor dissociation that it keeps other opioids from acting at receptor sites. It will even displace prior opioids from those same sites, and because buprenorphine has lower receptor activity despite its high affinity, the end result can be the development of a withdrawal syndrome in patients on other opioid agonists who are given buprenorphine. This is mistakenly thought to be secondary to the naloxone component but is directly attributable to buprenorphine, particularly since no significant amount of naloxone is absorbed transmucosally or by ingestion.

Physicians prescribing either methadone or buprenorphine should have a preliminary discussion with their patients regarding contingencies for increased pain. If patients are facing elective procedures that will likely produce at least moderate pain, it is the author's preference to have a discussion with the proceduralist or the anesthesiologist regarding pain management in patients on methadone or buprenorphine. In patients on methadone, the task is relatively simple. The maintenance dose of methadone should be continued in a single morning dose when possible. If the patient is to have nothing by mouth, methadone can be given intramuscularly, but the total dose should be approximately half the oral dose, because of a 50% hepatic first-pass metabolism, and then given in divided doses (e.g., an individual on 120 mg of oral methadone who is NPO may receive a total of 60 mg, given as 15 mg every 6 h or 20 mg every 8 h).

The patient can then be given the acute pain drug the physician prefers, but required doses may be at least 50% higher than usual and are often two to three times the usual doses for opioid-naïve patients (and occasionally may be even higher). If the pain is likely to be of relatively short duration, the maintenance dose of methadone may not need to be changed; however, if the patient is on appreciable doses of short-acting drugs for several weeks, an adjustment in methadone dose may need to be ordered as the acute pain drug is tapered. Giving multiple long-acting opioids has the potential for overlapping peaks and producing over-sedation and should be avoided when possible. If multiple long-acting drugs are used, patient education regarding the timing of the doses is important.

There are several strategies which may be successful in the treatment of short-term pain in the methadone or buprenorphine maintained patient.²⁹ The simplest of these is to maintain the buprenorphine dose prior to and through the period of postoperative or traumatic pain while adding a very high affinity, high potency opioid (fentanyl, sufentanil, hydromorphone), usually in significantly elevated doses, although it should be carefully titrated, starting at doses 50% to 100% higher than usual, and evaluating response and adjusting accordingly. This may particularly be appropriate in patients maintained on relatively low doses of buprenorphine, from 2 mg to 12 to16 mg per day.

In patients on higher doses of buprenorphine (i.e., >16 mg per d), it is thought best to discontinue buprenorphine, tapering it so that the last dose is given at least 48 hours (and the author's experience has shown that 72 hours or longer is desirable) prior to the planned procedure. The patient may then be maintained on a standard agonist, such as oxycodone IR, in doses ranging from 5 to 30 mg four times daily. Following the procedure, higher doses or a more potent drug (sufentanil, fentanyl, hydromorphone) can be used for analgesia. When the need for the acute pain treatment has passed, the medication may be tapered, and the patient referred back to the buprenorphine provider to resume treatment.

A third option is to use buprenorphine itself for pain treatment in these patients. However, this is rarely successful in patients already on higher doses of buprenorphine (24-32 mg/d) because of the ceiling effect of the drug and because buprenorphine is not as effective in moderate-severe to severe pain. However, in patients undergoing dental surgery or other moderately painful procedures or in those who are trauma victims, the use of additional buprenorphine 4 to 8 mg sublingually every 4 to 6 hours may be an effective pain management tool if the total dose does not exceed approximately 32 mg per day. One drawback to this strategy is that if buprenorphine is not effective in treating the pain, very high doses of fentanyl, sufentanil, or hydromorphone may be necessary to manage the pain. In some cases, patient monitoring with careful attention to respiratory rate and effort, as well as oxygenation, may become critical.

Patients on agonist treatment for addiction are at very high risk of relapse to “street” opiates or their other drugs of choice during these times of both severe pain and high stress. Involvement of supportive family and/or significant others, sponsors, and therapists may be important proactively, with the patient having a “safety plan” spelled out in advance.

Acute trauma may be more difficult to deal with because of the immediacy of the issue and the inability to plan in advance. It is wise to have the patient carry an emergency card or have a Medicalert^® bracelet to provide treaters with necessary information, as well as an emergency number to contact the involved medical personnel. The use of injectable nonsteroidal anti-inflammatory drugs, such as ketorolac, as well as local anesthetic in regional or field blocks, may all be highly useful. The rapid titration of short-acting opioids such as fentanyl or hydromorphone can provide appropriate analgesia, starting near usual doses and escalating as needed, even in patients on high doses of methadone or buprenorphine. In severe cases, conscious sedation or achieving a light anesthetic state with benzodiazepines may be necessary, and rarely general anesthesia is required to achieve control of pain and pain-related behaviors. Again, careful monitoring of respiratory status, oxygenation, and mental status may be necessary. One particularly difficult group of patients is those who are on buprenorphine and present with major trauma or the need for emergency major surgery. Because tapering of buprenorphine is not an option, the buprenorphine may be stopped on admission and pain treated with high doses of potent opioids. However, these patients need close monitoring since they will be susceptible to respiratory depression when the buprenorphine wears off.

CONTRACT VIOLATION AND TREATMENT TERMINATION

The author has given a series of talks for many years titled “Don't put people on meds you don't know how to take them off of” but has settled on the shorter and perhaps more elegant title “Don't take off when you don't know how to land.” Pain physicians and those dealing with patients with opioid addiction have had very different experiences in discontinuing opioids (and other dependency-producing drugs, especially benzodiazepines) in their patients. Review articles and textbooks frequently recommend relatively short tapering schedules for patients having opioids reduced and discontinued. This may be particularly effective in patients with opioid-induced hyperalgesia, where dose reduction may actually result in improved pain relief.

It has been the author's experience that patients with CD are far more sensitive to the dysphoria as well as to the physical manifestations of opioid withdrawal. The average patient undergoing therapeutic methadone detoxification may be withdrawn over a period of 6 to 12 months. However, shorter periods of detoxification may be well tolerated, but rarely at reductions of more than 10% of the dose per week, resulting in an approximately 3-month taper. This becomes an issue in those patients who are being dismissed because of problematic or aberrant behaviors, when continued prescribing is deemed unwise and/or dangerous.

Every pain physician or program should and must come up with treatment agreements that fit the needs of patient and the program. Sometimes, however, pain physicians do not differentiate between “yellow” flags, which should require refinement of the treatment agreement, and the use of predescribed contingencies (e.g., increased visits, more urine screens, involvement in counseling, or others), and “red” flags that may require dismissal from treatment. The period of dismissal may range from immediate and without detoxification for severe infractions to 30-day supplies of medication with instructions to find a different provider.

There is a widespread and incorrect assumption that opioid withdrawal is relatively minor and has few medical consequences. It is frequently compared with having a moderate viral syndrome, with diffuse pain, myalgias, arthralgias, shaking chills, nausea, vomiting, and diarrhea, and lasting a relatively short time. This may be true for younger, healthier patients taking only short-acting opioids. However, in older and more medically/psychiatrically complex patients, and in particular with the use of longer-acting SR opioids in higher doses, withdrawal may be severe and protracted, lasting weeks and even months.

Elevated pulse and blood pressure may be present and result in cardiac decompensation in those with underlying heart disease, including the development of angina and myocardial infarction. Vomiting may be severe and result in aspiration, esophageal tears with bleeding (Mallory Weiss syndrome), volume contraction, and severe electrolyte and acid-base balance issues, including acute tubular necrosis with renal failure. This may also occur with severe diarrhea. True informed consent should require that the prescribing pain physician discuss these possibilities with patients early in the treatment course and when treatment agreement violations are noted so that it may have a deterrent effect on further aberrant behaviors.

An issue that may result in treatment agreement violation is that of positive urine or salivary drug screens. Such positive screening tests should be subjected to appropriate confirmatory testing before taking action, as appropriate. Gas chromatography and mass spectroscopy (GC-MS) are the usual confirmatory tests, but other tests (such as double liquid chromatography followed by mass spectroscopy or in some cases thin layer chromatography, depending on the substance involved) may be appropriate. Chain of custody issues and false-positives from interfering substances should be considered as well. Drug testing is ideally an adjunctive test, and in cases where the clinical behaviors have not been aberrant and a positive drug test occurs with the patient denying its validity, consideration should be given to the potential for a false-positive.

Termination, particularly without detoxification, should be the final decision when no safe and effective treating of the patient remains. Adjunctive medications to ameliorate withdrawal, such as the use of α-2 agonists (clonidine, guanfacine, and guanabenz), as well as antidiarrheal and antiemetic agents, should be strongly considered and prescribed.^30-32 If a 30-day supply of opioid medication is given, it may be appropriate that it be written in a tapering dose schedule over that period of time. If benzodiazepines are prescribed, tapering doses of longer-acting, more slowly absorbed agents such as clonazepam or chlordiazepoxide may be indicated. Use of diazepam, alprazolam, and lorazepam, which are more rapidly absorbed and have high abuse potential, should be avoided. Anticonvulsants, such as carbamazepine, valproic acid, and gabapentin, in usual therapeutic doses for seizures, may also be used to aid patients in withdrawal from benzodiazepines.^33-35

It is not uncommon for patients to be referred to a detoxification facility. If this occurs, it is worthwhile for the pain physician to have determined programs in advance that would meet the patients’ needs. Many detoxification settings are managed by nursing staff, often licensed practical nurses with registered nurse supervision, having an off-site physician and prewritten protocols, with very little ability to individualize care. The author has seen hundreds of patients on appreciable doses of SR morphine, oxycodone, and other opioids given the same 5-day protocols using methadone, at doses no higher than 30 mg, then tapered over an additional few days. Such tapers are rarely, if ever, effective and leave patients with a moderate to severe and often protracted course of opioid withdrawal.

Many physicians are not aware of the nature of free-standing (so-called “public”) detoxification facilities. Patients are evaluated and treated by nursing staff (often licensed practical nurses, with no registered nurses on site) on the basis of standing orders, and many, perhaps most (or even all) patients in these programs are not seen by a physician. The facility may have a very limited formulary, so that patients on medications they do not stock have to arrange to bring these medications, or have them brought by friends or family. Many facilities take a “one size fits all” approach and will take patients off all dependency-producing medications even if one or more of those medications has not been problematic (e.g., the physician may refer the patient because of benzodiazepine or alcohol abuse and the patient has been adherent to the opioid treatment; however, the program will taper them off of all their drugs, including the opioids).

There are generally hospital-based detoxification programs with on-site physicians and stronger nursing presence where a more individualized approach to these complex patients can be taken. Pain physicians and programs should take the time and effort to familiarize themselves with appropriate detoxification settings and trained physicians in their community, or within referral distance, where there is a greater likelihood of a safe and successful outcome. The American Society of Addiction Medicine (www.asam.org), the American Academy of Addiction Psychiatry (www.aaap.org), and the American Osteopathic Academy of Addiction Medicine (www.aoaam.org) have listings of members on their websites for referral.

In patients for whom opioids have been effective in management of pain but where the patient self-escalates doses or engages in other aberrant behaviors necessitating treatment termination, consideration should be given to referral to a buprenorphine prescriber. In some pain programs, the pain physicians have colleagues who have taken an approved buprenorphine training course and have a prescribing waiver. The sublingual forms of buprenorphine, Suboxone (available now only in the proprietary filmtab), and Subutex (available recently as a generic preparation), are not approved for pain treatment. However, in the patient with combined pain and addiction, they may prove useful in overall patient management, and as long as the patient has documentation of opioid dependency, buprenorphine can be legally prescribed. The combined buprenorphine/naloxone preparation is thought to be safer and less likely to be misused/abused, particularly by injection, and should be the first choice of most patients.

The author has treated many patients who were difficult or impossible to manage with usual SR opioids (particularly OxyContin and generic immediate-release and/or sustained-release oxycodone preparations), who became well managed without dose escalation and with tremendous improvement in compliance and quality of life with the use of usual doses of buprenorphine. In management of addiction, buprenorphine can usually be given once daily, but as with methadone, pain management is better accomplished with multiple divided doses. Again, combination buprenorphine/naloxone (Suboxone filmtabs) is considered safer, has less abuse potential, and is preferred.

Pain physicians may prescribe sublingual buprenorphine for pain, with or without a waiver, as an off-label use of the medication. However, it must be emphasized that there are few studies of its use for this indication, and full informed consent by the patient is important. In addition, both insurance companies and pharmacists may be unwilling to dispense the medication when the prescriber does not have a federal buprenorphine waiver or if it is for an off-label indication However, since these patients have both pain AND addiction, appropriate prescribing can generally be accomplished. Therefore, writing the words “for pain” on the prescription may be helpful. A letter from the Drug Enforcement Agency (DEA) to the chair of the ASAM pain committee indicated that physicians may legally use buprenorphine for pain treatment off label and without a special waiver.³⁶

TOOLS FOR DEALING WITH PATIENTS WITH CHEMICAL DEPENDENCY

Unfortunately, it has been all too frequent in the author's experience that the identification of past or present CD is tantamount to dismissal of the patient as inappropriate for a pain management program. Such identification should ideally lead to the creation of an appropriate treatment agreement that applies the necessary contingencies so that these patients can be safely managed. As has been previously stated, the American Pain Society, the American Academy of Pain Management, and the American Society of Addiction Medicine in a common public policy statement, emphasized this point several years ago.²⁸ Fear of regulatory action, legal problems, and civil lawsuits are not adequate reasons to deprive patients in need of adequate pain management. Strategies for doing so have been discussed in the appropriate sections above.

There has been a dramatic increase in the number of medications available to treat chemically dependent patients for many different drugs of choice. While most of the approved drugs have been for combating alcohol use and craving (Table 70-4), there are several approved for opioids as well (buprenorphine and methadone have been discussed). Several medications have been studied for other forms of CD, such as cocaine and other stimulants, which have not yet been approved but are available off-label, and may be useful in specific patients. Table 70-2 lists the approved medications for treatment of opioid dependency, as well as investigational agents for other indications. There are several excellent reviews of these medications.^37,38

A. ALCOHOL

Disulfiram

The oldest medication developed for the treatment of alcohol craving and abuse is disulfiram (Antabuse). This medication works by blocking acetaldehyde dehydrogenase, which is produced by alcohol dehydrogenase in the metabolism of alcohol to acetic acid and water. Acetaldehyde accumulates and causes nausea, vomiting, headache, flushing, and lightheadedness and may result in significant hypotension and syncope.^39,40

Disulfiram does not have direct effects on craving but rather works as a deterrent to drinking. However, studies of self-administration have shown little effect, and in order to be effective, disulfiram should be monitored by a third party, which may be a motivated spouse, friend, supervisor, or coworker. Disulfiram should be prescribed only when there is no ethyl alcohol present; a blood alcohol concentration (BAC) should be checked, or a minimum of 24 hours should have passed since the last drink.

Although it is generally effective in a dose of 250 mg daily, patients may require doses of 500 mg per day. In monitored settings, disulfiram may be given in doses of 500 mg on Monday and Wednesday, with 750 mg on Friday. However, GI intolerance, with nausea, vomiting, and diarrhea, may increase at higher dose levels. It is critical to discuss with prospective patients disulfiram side effects and to warn against accidental alcohol exposure, which may be associated with foods (wine vinegar, alcohol used in cooking), liquid medications preserved with ethyl alcohol (cough and cold medications and others), and rarely exposure to alcohol in perfumes and colognes. In addition, breathing in the fumes of alcohol-based skin sanitizers (Purell and others) by washing hands close to the face, can result in absorption of alcohol.

Unsupervised disulfiram treatment has relatively poor results.³⁹ However, monitored treatment where a responsible individual in the home, workplace, or elsewhere directly observes the patient taking the medication daily (or three times weekly in higher doses) may have better results. This has been especially effective in impaired professional programs, in which physicians, nurses, and other health care professionals with alcohol addiction are mandated by their licensing boards to take disulfiram under supervision.

Disulfiram reactions are usually self-limited but in severe cases may require IV fluids, and there are anecdotal reports of the benefit of antiemetics, antihistamines, and ascorbic acid; the author has had good experience giving sublingual aspirin.⁴¹ In individuals with underlying coronary heart disease, peripheral arterial disease, and cerebrovascular disease, however, hypotension associated with disulfiram reactions may be more problematic. Disulfiram also blocks dopamine β-hydroxylase, an enzyme involved in cocaine metabolism, and there are ongoing studies of its use for this indication.

Acamprosate

Acamprosate is a homotauric acid derivative that modulates glutamatergic transmission by antagonizing the N-methyl-D-aspartate (NMDA) pathway in the CNS and appears to reduce the severity of postacute withdrawal syndromes in newly recovering alcoholics. This has an important effect on reducing alcohol craving. Several studies^42,43 have shown benefit of acamprosate. However, a large multisite study, Project Combine, failed to show statistically significant benefits of acamprosate.⁴⁴ The author believes that acamprosate resulted in a higher level of complete abstinence in a smaller group of individuals, while naltrexone (see below) resulted in more sustained reduction in drinking in a larger group of patients; however, there was a lower rate of total abstinence.

Acamprosate is remarkably free of side effects, with mild GI symptoms only, which generally abate. However, it has to be taken as 666 mg (two 333-mg tablets) three times daily for efficacy. It has no known drug interactions and may be combined with disulfiram or naltrexone to increase effects on alcohol craving. Although there are no published studies showing benefit of such drug combinations, the author has used them in many patients with good effect.

Naltrexone

Naltrexone has been discussed above and obviously is contraindicated in patients who are receiving opioids or for whom opioid treatment is contemplated. However, in alcoholic patients at high risk for relapse in whom non-opioid pain treatment is contemplated, naltrexone may be very useful in preventing relapse.^44-46 Although the mechanism is not clear, it appears that alcohol works, in part, by the production of adduction products, tetrahydroisoquinolones (THIQs), which have opioid activity. Blocking this effect reduces the reinforcing activity of consuming alcohol, and individuals on naltrexone, if they have a brief drinking episode (a “slip” or “lapse”), are far less likely to develop a full relapse (a fall). Doses of 50 mg daily, or 100 mg on Monday and Wednesday with 150 mg on Friday in a monitored setting, are generally effective. Nausea and vomiting are the major side effects, and these decrease with continuing use in most patients.

While there is a “black box” liver warning in the prescribing information, there are no reported cases, of this drug causing hepatic toxicity in current doses; prior studies using 250 to 500 mg per day were associated with rare cases of very high transaminase levels, and it is recommended that ALT/AST be monitored prior to administration and that three times upper limits of normal (ULN) be considered a relative contraindication to prescribing or continuing naltrexone.

Naltrexone is also available as a SR injection (Vivitrol^®), which is given every 4 weeks. It is a deep IM injection, generally given in the gluteus maximus muscle, and injection site pain, swelling, and rarely infection may occur.^47,48 The monthly injection has fewer gastrointestinal (GI) side effects and is generally well tolerated and eliminates the compliance issues with daily use of the medication. Pain in those on naltrexone can be treated similarly to that described for patients taking methadone and buprenorphine (see above and reference 29).

Additional Medications

While disulfiram, naltrexone, and naltrexone ER (Vivitrol^®) are approved for the treatment of alcoholism, there are several medications in clinical trials that have shown benefit but would be off-label if given for that indication. Topirimate has been extensively studied for alcohol⁴⁹ and cocaine and other stimulant abuse.^50,51 Dosing for topirimate is similar to that used in treatment for seizure disorders and migraine prophylaxis, and the side effects and precautions are similar. Ondansetron has had results comparable to naltrexone, but only in Cloninger type 2 (Babor type B) alcoholics (e.g., men with strong family histories of alcoholism, early onset disease, and high levels of psychopathology and criminality).⁵²

A large number of medications and herbal preparations have shown some effects in small, open label studies (e.g., St. John's Wort, kudzu root), but the risk/benefit ratios for these are unknown, and they should all be considered investigational at this time. Combinations of antidepressants (particularly SSRI and SNRI agents) with anticraving drugs have been used successfully, particularly in patients with underlying mood disorders. Studies of combinations of gabapentin and naltrexone have also yielded positive results. However, many of these studies are smaller, open-label trials and have not been replicated in larger multicenter randomized controlled trials. Caution is indicated, and these agents should not be first-line considerations at this time.

COCAINE AND OTHER STIMULANTS

There are no approved medications for individuals who abuse cocaine and stimulants. Psychosocial treatment, with medication as needed supportively (e.g., brief use of anxiolytics), and treatment of underlying psychiatric disorders are the standards of care. In individuals whose triggers to abuse cocaine and stimulants are other drugs, such as alcohol or opioids, the use of agents to reduce craving may result in reduction of cocaine and stimulant use.

Topirimate has shown positive early results in trials for decreasing cocaine use and craving⁵⁰ as well as methamphetamine use.⁵¹ In patients who may have alternative indications for topirimate, such as a seizure disorder or migraine prophylaxis, it may be more of a first-line drug in the presence of cocaine or other stimulant abuse. Disulfiram, described above for alcohol dependence treatment, may have utility in reducing cocaine craving, perhaps secondary to its effects on blocking dopamine-β-hydroxylase as well as acetaldehyde dehydrogenase.⁵³

The use of amantadine, rimantadine, bromocriptine, and tricyclic antidepressants (particularly desipramine) has waned because of little evidence of sustained effects from any of these agents. There is ongoing investigation of N-acetylcysteine,⁵⁴ baclofen,⁵⁵ and other agents, but their use is considered investigational at this time. Early work on a cocaine vaccine has yielded positive results.⁵⁶ A large number of agents have been tried with initial success in small, open-label studies, but positive results have not been found in larger, randomized, controlled studies. The physician is encouraged to follow the current literature.

DRUGS USEFUL IN TREATING OPIOID-DEPENDENT PATIENTS

In opioid-dependent patients who are in treatment for pain where prior experience has shown that opioids cannot be used safely or for those patients in recovery from opioid dependency who would prefer not to receive opioids, consideration can be given to opioid-blocking agents (Table 70-4). Oral naltrexone has been approved for this indication since 1992. The depot IM form (Vivitrol) was approved for this indication in 2010. Although oral naltrexone has a significant number of studies indicating its long-term safety and efficacy in this population,^57,58 the depot form was approved on the basis of relatively limited studies^59,60 and its long-term effects have not been reported, with caution being urged.⁶¹ It is critically important with both agents (oral and IM naltrexone) that patients are completely detoxified from opioids prior to administration, because each may precipitate a severe and potentially life-threatening withdrawal syndrome in the incompletely detoxified patient. Precipitated withdrawal is different from naturally occurring withdrawal, with delirium, seizures, severe agitation, vomiting, aspiration, and other complications, all of which have been witnessed by the author.

In patients who are leaving long-term residential treatment or those who have been incarcerated for long periods of time, the use of depot naltrexone may be useful in promoting abstinence from opioids, with no risk of precipitated withdrawal. However, in more recently detoxified individuals, the author has seen several cases of severe, intractable, and psychotic depression in patients receiving depot naltrexone; the cause, however, is not clear. In addition, the use of these agents may foreclose the option of using opioid treatment, particularly with the depot form, since the blockade may last 4 or more weeks. However, techniques as described above can be used to treat acute or subacute moderate to severe pain in these patients.²⁹

Physicians who prescribe opioids to patients on long-term agonist therapy should be aware that there may be a receptor hypersensitization in these patients, with exaggerated responses to even small, therapeutic doses of opioids. If patients who have been on naltrexone or depot naltrexone are to be treated with opioids, caution should be used, with very low doses of medication prescribed, even lower than those given to opioid-naïve patients. A recent event in the Boston area involved a physician who had prescribed depot naltrexone to several hundred patients and had to leave his practice immediately. A number of the patients were unable to locate alternative prescribers and relapsed to opioid use. There were several anecdotal reports of serious overdoses in these patients, sometimes with extremely modest doses of opioid.

MISCELLANEOUS DRUGS OF ABUSE

Other drugs, including cannabinoids, hallucinogens, inhalants, and others, generally do not require detoxification, and no approved medications are shown to improve outcomes. Treatment of target symptoms, using neuroleptic agents, benzodiazepines, and supportive human contact in a calming environment, is generally sufficient. In most cases, intoxication is self-limited, and drug craving is treated supportively. Again, careful evaluation and treatment for underlying psychiatric disorders are essential. In addition, many drugs can produce neuropsychiatric abnormalities, and therefore, specialized evaluation and testing may be necessary.

CONCLUSION

The world of patients with pain and the world of patients with CDs are not two separate universes but rather a Venn diagram with significant overlap. Many patients develop CD as a response to unremitting chronic pain. A number of patients being treated for pain have underlying CD or its risk factors or develop CD during their pain treatment. The pain physician and the addiction medicine/psychiatry practitioner need to develop and use the tools to deal with the alternative problem in their patient population.

This requires both types of practitioners to develop a greater expertise in both areas than might be expected of the average generalist. It also should require a familiarity with the needed expertise that is available in the immediate vicinity of the practitioner in the form of individuals and programs that are well suited for the management of addiction in the pain patient and pain in the patient with addiction. Because neither pain programs nor addiction programs are created equal, it is well worth the time and effort to familiarize oneself with the available resources and refer to the most appropriate resource when needed.

There has been exciting progress in the development of personal medicine, with evidence that response to some anticraving medications may relate to genetic host factors. The efficacy of naltrexone, for example, differs among individuals with different single nucleotide polymorphisms (SNPs) of the dopamine gene.⁶² Pain and addiction treatment clinicians should remain current with progress in this important area. All too often, the recognition of underlying or newly developed CD in a patient in a pain program is seen as an indication for dismissal rather than as a challenge and an opportunity to treat both issues. Pain physicians and addiction medicine physicians need to interact formally and informally to a far greater degree than is now the case in most programs. The prescription drug epidemic, which has increased since the late 1990s, will not allow for a fragmented approach to this population. It is hoped that this chapter will contribute in some way to that increased collaboration.

REFERENCES

ADDITIONAL GENERAL READINGS IN ADDICTION MEDICINE/PAIN

INTRODUCTION

Urine drug testing (UDT) is considered one of the mainstays of adherence monitoring in conjunction with prescription monitoring programs and other screening tools; however, UDT is associated with multiple limitations secondary to potential pitfalls related to drug metabolism, reliability of the tests, and the knowledge of the pain physician.¹ The practice of UDT is more common in a noncancer pain setting than in an oncology or primary care setting; however, it may be utilized in a punitive manner in efforts to “catch” the patient with an inappropriate positive or negative screen result. Unfortunately, this often results in dismissal of the patient from the practice. Drug testing is most commonly used for two reasons: to identify substances that should not be present in the urine (forensic testing) and to detect the presence of prescribed medications (compliance testing).

URINE DRUG TESTING IN CHRONIC PAIN PATIENTS ON CHRONIC OPIOID THERAPY

The use of UDT to monitor patients on chronic opioid therapy (COT) treated in a pain clinic is reasonable; however, this testing is not mandatory for all patients on COT in all settings. The use of UDT should be based on the clinical judgment of the prescribing clinician; however, some clinicians and/or clinics test all patients on COT sporadically based on policy. Katz and Fanciullo² propose that although further research is needed, it may be easier and more uniform to conduct routine urine toxicology testing in all patients with chronic pain treated with opioids. By adopting a uniform policy of testing, stigma is reduced while ensuring that those persons dually diagnosed with pain and substance use disorders receive optimal care. With careful explanation of the purpose of testing, patient concerns can be easily addressed.^3,4

Abnormal UDT results of patients on COT in a chronic pain clinic generally include absence of the prescribed opioid, presence of nonprescribed drugs, presence of illegal drugs, and adulterated urine specimens.⁵

Fishbain and colleagues gathered urine toxicology results among 122 patients who were prescribed opioids for noncancer pain and found abnormal results in 43% of this sample.⁶ Michna and colleagues published a report on 226 patients primarily with chronic back pain and found 46.5% of the sample to have abnormal urine toxicology.⁵ In a retrospective study of 470 patients, 4 of 10 patients prescribed opioids also had abnormal urine toxicology.² In 2003, Katz and colleagues reported that approximately 20% of patients with persistent pain on COT who seem compliant will test positive for an illicit drug and/or another non-prescribed opioid.⁷ Cone et al. analyzed a large number (n = 10,922) of urine samples from patients with persistent pain on COT and found that the overall prevalence of illicit drug use was 10.9%.⁸ The illicit drugs found in the urine of these patients most often were marijuana, cocaine, and ecstasy-related drugs.⁸ Couto and colleagues reported that over 30% of UDT results in chronic pain patients contained at least one other controlled substance in addition to the prescribed opioid.⁹ These studies underscore the importance of urine toxicology testing along with behavioral observation and self-report measures to help identify aberrant drug-related behaviour.¹⁰

METHODS OF URINE DRUG TESTING

The health care professional (HCP) must know which drugs to test for and by what methods, as well as the expected use of the results. Manchikanti and colleagues¹¹ studied the diagnostic accuracy of POC testing with immunoassay compared to laboratory testing with chromatography in 1000 patients. Compared with laboratory testing for opioids and illicit drugs, immunoassay in-office testing has high specificity and agreement but variable sensitivity, which demonstrates the value of immunoassay drug testing; however, a cautious approach is advocated. Agreement for prescribed opioids was high with the index test (80.4%). The reference test of opioids improved the accuracy by 8.9% from 80.4% to 89.3%. Urine drug testing should not be confrontational, but rather both clinicians and patients should view UDT like any other laboratory test. Because UDT may support or trigger the clinician's suspicions about aberrant drug-taking, it is information that the clinician must view with other factors to see “the whole picture.” The clinician must be aware of the limitations of these tests (e.g., low sensitivity of immunoassay for semisynthetic and synthetic opioids). Confirmatory tests should be specifically requested. If the purpose of testing is to find unprescribed or illicit drug use, combination techniques such as gas chromatography and mass spectrometry (GC/MS) or high-performance liquid chromatography (HPLC) are most specific for identifying individual drugs or their metabolites.¹²

Caveats to the use of UDT include the following:

1. Ensure the proper collection, handling, and documentation of the urine specimen.

2. Be knowledgeable regarding interpretation of UDT results.

3. Know specifically what your patient consumed and when it was consumed prior to the urine collection.

4. Know what you are looking for and what you will do when various results come back.

One of the most common urinary drug screens involves fluorescence polarization immunoassay, which detects the “federal five” of marijuana metabolite (delta-9-THC), cocaine metabolite (benzoylecgonine), opiates, phencyclidine (PCP), and amphetamines/methamphetamines. The test has a relatively low sensitivity for semisynthetic and synthetic opioids (e.g., hydrocodone, oxycodone, fentanyl). Therefore, if the test on the patient's urine is negative for the presence of one of these drugs, it does not exclude use. Furthermore, even if the test is positive for a specific drug, a confirmatory test should follow. The confirmatory UDT is based on principles of GC/MS or HPLC. The gold standard is considered to be the GC/MS. The expanded “federal ten” also tests for methadone, propoxyphene (no longer available), methaqualone, benzodiazepines, and barbiturates.

High-performance liquid chromatography (HPLC) uses a stationary phase (usually hydrophobic saturated carbon chains) contained in a stainless steel column in order to help separate, identify, and quantify compounds based on their particular polarities and interactions with the column's stationary phase. Other components may involve a pump providing high pressure to move the mobile phase (e.g. buffered organic solvent mixture) and a detector. The analyte retention times are variable and may be affected by the strength of interactions with the stationary phase as well as the ionic strength and flow rate of the mobile phase. When coupled with multiple mass spectrometers [MS] (e.g., HPLC/MS/MS), these techniques may be particularly effective to identify compounds in UDT.

Care must be taken in the collection of the urine specimen and in ensuring that the “handling chain”/“chain of custody process” to the lab is executed and documented properly. The collection facility should be a private area with no sink basin or access to water/liquids, and the toilet should have pigmented toilet water (e.g., blue). Measurements of urinary creatinine, pH, specific gravity, and temperature should also be ordered and recorded to assist with results interpretation and to increase specimen reliability. To confirm reliability and authenticity of the urine sample, values for each of the variables should be within the following limits:

• Temperature (within 4 minutes of voiding): 90°F to 100°F

• Urinary pH: 4.5 to 8.0

• Urinary creatinine: 20 mg/dL

Additionally, Specimen Validity Testing (SVT) to determine if adulterants/foreign substances were added to urine or if the specimen was substituted should occur (e.g., testing for nitrite, pyridine, glutaraldehyde, bleach, soap). Adulterated specimens may be suspected if nitrate is ≥500 mcg/mL, or pH is ≥11, or exogenous substances are present, or substances are present at significantly higher concentrations than normal physiologic concentration (e.g., chromium + 6 in significant supraphysiologic concentrations).

Appropriate interpretation of UDT is vitally important. Clinicians should appreciate the potential metabolites of the various opioids that their patients are taking (Table 71-1). Reisfield and colleagues concluded that family physicians who ordered UDT to monitor patients with persistent pain on COT were not proficient in their interpretation.¹³ Nafziger and Bertino described the following factors that may affect the results of UDT: cutoff selection; pharmacogenetics [ultra-rapid metabolizers]; laboratory technology; and subversion/adulteration of the urine specimen¹⁴ (Table 71-2).

URINE DRUG TESTING IN CLINICAL PRACTICE

Starrels and colleagues performed a systematic review of treatment agreements and UDT in efforts to reduce opioid misuse in patients with chronic pain and found that evidence was weak in supporting the effectiveness of opioid treatment agreements and UDT in reducing opioid misuse by patients with chronic pain.¹⁵ Although there does not exist robust/rigorous evidence that UDT positively affects outcomes, a number of authors^5,6,8,16-19 demonstrate that UDT provides valuable information to make clinical decisions and care for patients with persistent pain on COT. Opioid misuse in patients with persistent pain on COT may have a variable and wide-ranging prevalence of 3% to 40%.^20-22 Manchikant et al. gave evidence that UDT has good diagnostic accuracy; is helpful in identifying noncompliance, opioid misuse, and/or use of illicit drugs; and may decrease prescription drug abuse or illicit drug use for patients with persistent pain on COT.²³

Gupta and colleagues retrospectively reviewed physician opioids prescribing practices in patients with aberrant behaviors for patients at an academic center's chronic pain outpatient clinic and assessed what occurred after they interpreted the patient's UDT results.²⁴ The urines were categorized as having urine screens that were normal (expected findings based on their prescribed drugs) or abnormal. Abnormal findings were those with: 1) absence of a prescribed opioid; 2) presence of an additional nonprescribed controlled substance; 3) detection of an illicit substance; 4) adulterated urine sample.

When an aberrance occurred, it was most likely in the form of an abnormal UDT, followed by the presence of an illicit drug, and then self-escalating doses, with other types of aberrance comprising a small fraction of the total.²⁴ Health care provider (HCP) responses to this aberrance generally took the form of five basic types, with a smaller percentage of patients not returning to the clinic and therefore effectively discharging themselves. Of note, the preferred response to the discovery of aberrant behavior was to continue to prescribe opioids. This occurred approximately 55% of the time.²⁴ Discontinuation of opioid therapy was a distant second at roughly 20% of the responses (Fig 71-1) (even with instances in which the same patient had aberrant behavior on multiple occasions). Thus, it appeared that despite their interpreting UDT as abnormal with the presence of an illicit drug, most physicians continued COT without significant changes in treatment.

Barth and colleagues retrospectively reviewed medical records of patients on chronic opioids for longer than than 22 months in a primary care clinic and determined that patients on chronic opioids who have a UDT positive for an illicit opioid or unprescribed opioids are more likely to respond to monitored opioid pharmacotherapy.²⁵ Patients with a UDT positive for cocaine, alone or in combination, are less likely to resolve aberrant behavior within the structure of a monitored opioid pharmacotherapy program and are more likely to be discharged electively or administratively from the program without significant transition to addiction treatment.²⁵

Physicians, specifically those in pain management settings, often believe that UDT may be helpful when utilized routinely to establish baseline information regardless of how much information is available from physicians, prescription monitoring programs, and other sources. In 2008, the Biomedical Research and Education Foundation (BREF) conducted a study based on a questionnaire distributed to 250 attendees of the American Congress of Pain Medicine in New York City.²⁶ Forty-nine attendees completed it (n = 49), most consisting of anesthesiologists, primary care physicians, and physiatrists. When selecting patients for urine testing, some respondents tested all patients who were being prescribed a controlled substance, while others tested a subset of that group. Seven respondents (14%) did not use UDT, 34 (69%) tested only patients who displayed aberrant behavior/drug-taking, and 25 (51%) tested patients that they were considering prescribing a controlled substance for.

The patient population subjected to urine drug testing varied from 0% to 25% of patients (testing practice of 38.8% of respondents) to testing 76% to 100% of patients (22.4% of respondents). The frequency of testing in the survey appears to be most frequently random (“other” as opposed to a calendar-oriented schedule—23 respondents [47%]), but some respondents reported testing monthly (16%)²⁷ or quarterly (10%).²⁷ Five respondents performed biannual testing and six (12%) said they tested annually. Testing was sometimes scheduled, but might also be driven by a specific patient action or change in treatment.²⁶

Caution must be exercised in interpreting UDT results in a pain practice. True negative urine results for prescribed medication may indicate a pattern of bingeing rather than drug diversion. However, the clinician must not jump to the conclusion that because the laboratory reports a negative test result for the opioid for which the patient is being prescribed, the patient is not taking the opioid. Possible scenarios to explain this include the patient is an ultra-rapid metabolizer of this opioid, bacterial contamination lead to a lower opioid level in the specimen, and a random urine sample with a slightly lower specific gravity (e.g., if the concentration of the opioid is subthreshold, such as 199 ng/mL with a cutoff of 200 ng/mL, the test will be negative for that opioid). If the concentration of the opioid is roughly one-half that of the expected value, possible scenarios include the patient is a rapid metabolizer of the opioid, or the patient is taking a lower dose of opioid because of miscommunication, or the patient is doing well with less pain and decreased the dose but did not inform the pain specialist, or the patient is taking one-half his or her dose and selling the rest. Time of last use of the drug(s) and/or serum drug testing for the opioid prescribed can be helpful in interpretation of the results.

In specific patients, UDT may detect traces of unexplained opioids secondary to drug metabolism. For example, a patient taking codeine may show trace quantities of hydrocodone (≥11%) unrelated to hydrocodone use.²⁸ Detection of small amounts of hydrocodone in urine containing a high concentration of codeine should not be interpreted as evidence of hydrocodone misuse. In a patient who is prescribed hydrocodone, quantities of hydromorphone may also be detected due to hydrocodone metabolism.³ Morphine may be metabolized to produce small amounts of hydromorphone (≥10%) through a minor metabolic pathway.²⁹ Quetiapine (Seroquel) may produce false methadone-positive urine drug screens.³⁰

Normetabolites such as norcodeine, norhydrocodone, and noroxycodone are metabolites that are not available commercially. Consequently, detection of normetabolite in specimens not containing parent drug provides conclusive evidence that the parent drug was consumed.³¹ Cone and colleagues analyzed 2654 urine specimens of pain patients in a chronic pain clinic treated with COT. For specimens containing normetabolite, the prevalence of norcodeine, norhydrocodone, and noroxycodone in the absence of parent drug was 8.6%, 7.8%, and 9.4%, respectively. From one-third to two-thirds of these specimens also did not contain other metabolites that could have originated from the parent drug. The authors concluded that norcodeine, norhydrocodone, and noroxycodone may be useful in interpretation of opiate drug source and may reduce false-negative results that would occur without tests for these unique metabolites.³¹

Urine drug testing may be useful to identify patients who are “poor metabolizers” or “ultra-fast metabolizers.” Yee et al. evaluated the metabolism of oxycodone to oxymorphone in a pain patient population using a quantitative liquid chromatography-tandem mass spectrometry analysis of 32,656 urine specimens obtained from pain patients between March 2008 and February 2010.³² Urine samples containing oxycodone without oxymorphone allowed an estimation of the proportion of poor metabolizers (2.4 ± 2.1%) in the population. A similar analysis of samples containing oxymorphone without oxycodone gave an estimate of the proportion of ultra-rapid metabolizers (1.8 ± 1.1%) in the population; and showed that it may be possible to identify fast or slow metabolizers who may be at risk for adverse events.³²

SUMMARY

If UDT is utilized, it is crucial to avoid inappropriate interpretation of results, which may adversely affect clinical decision making. The HCP should not infer patient noncompliance or misuse of opioids based on positive or negative detection of opioid in the urine. Results of CDT in conjunction with other tools and clinical information are used when deciding whether to alter the treatment plan.

There is no uniform strategy to deal with specific abnormal results of UDT. Unexplained results should be verified and the discussed with the patient. Each practice should be comfortable dealing with abnormal results in a specific way, but it should be consistent for each practice. Patients found to have substance abuse problems should be referred immediately to an addiction medicine specialist for counseling and treatment. If COT is to be discontinued, it should be tapered gradually and replaced with non-opioid analgesic medications. Algorithms for UDT are available that may help certain clinicians/practices.^1,33 Furthermore, the options of what to do with abnormal results should be known in advance, and patients should be informed of these plans when they first become part of the practice (as long as the clinicians “stick to what they state”).

REFERENCES