Chapter 60. Common Opioid-Related Side Effects

This chapter discusses the special set of potential opioid-related complications. Objective signs and symptoms of chronic pain are hard to ascertain, whereas opioid use is associated with concrete signs and symptoms that may act as markers for opioid side effects. Most commonly, opioids produce constipation, nausea, vomiting, sedation, and respiratory depression. Any adverse effects from opioids may significantly limit therapy, and some can present with life-threatening consequences. Unfortunately, there are few predictors of which patients will experience which side effects and which particular opioids will produce them. It is sensible to expect side effects and to take preventive action. Since not all opioid-related toxicity can be predicted or prevented, patients should be closely followed with a high level of suspicion. Effective management includes anticipation of adverse effects when possible, use of preventive measures, and choosing the best medication with the optimum method of administration. Clear communication with the patient, family, or nurse to ensure prompt recognition and response to adverse effects is of utmost importance in order to recognize and prevent possible adverse effects of opioid treatment.

Constipation is the most common dose-dependent side effect of opioids. But unlike most other side effects, tolerance does not develop. Thus, constipation can be expected throughout the duration of opioid administration. Preventive therapy with cathartics and adequate fluid intake is a mainstay of therapy and should be offered at the time opioids are started and continued throughout opioid treatment. Stool softeners and bulking agents such as bran or psyllium derivatives alone will be inadequate because opioid-related constipation results from decreased gut motility. Therefore, active stimulating laxatives are effective and passive ones are not.

Severe constipation may respond to oral administration of naloxone, which is an opioid antagonist with specificity to bowel. Administration of oral naloxone has limited systemic bioavailability; however, it has increased concentration and efficacy in the gastrointestinal (GI) tract. Unfortunately, there is uncertainty about the dosing regimen. Opioid withdrawal has been observed when oral naloxone is administered at dosages exceeding 20% of the prevailing 24-hour morphine dose. It is suggested that initial individual oral naloxone doses should not exceed 5 mg. In our institution, we start with 1.6 mg to 2.4 mg taken orally (4 to 6 small ampules) every 4 hours until the first bowel movement, or for five doses. If ineffectual, we may try another series with a higher dose. However, constipation may be caused by factors other than opioids. Oral naloxone only works when the constipation is solely opioid-related.

Since constipation can be mitigated by direct effects of antagonists on the bowel, it is possible that opioids that are delivered without direct bowel contact induce less constipation. There is evidence that certain opioid products that are absorbed without contact to the GI tract, such as transdermal fentanyl, induce less constipation when compared with oral morphine at doses effecting the same degree of pain relief. A significant reduction in the use of laxatives has been reported. In one study of cancer patients, the incidence of constipation was reduced by up to two thirds after switching from oral morphine to transdermal fentanyl. These findings should be viewed with cautious optimism, as published studies to date have not included patients on standardized bowel care regimens. In a study by Donner et al (1996) comparing transdermal fentanyl with sustained-release morphine, the patients receiving transdermal fentanyl had a higher incidence of diarrhea. The authors speculated this occurred because 10% of the patients experienced opiate withdrawal symptoms when converting from sustained-release morphine to transdermal fentanyl. Some patients taking transdermal fentanyl continued to take laxative doses regularly as prescribed when they were previously on morphine, resulting in a sudden increase in defecation. It is unclear whether these findings apply to the other new opioid-delivery systems such as the transmucosal fentanyl system, since these products have some degree of oral absorption.

Although nausea and vomiting is a common early side effect of opioids, severe nausea and vomiting caused solely by opioids is rare. Addition of antiemetics or reduction of the opioid dose to the minimal acceptable level of analgesia is usually effective. A change in the route of administration may also alleviate symptoms. Fortunately, tolerance often occurs within several days of administering opioids, at which time antiemetic therapy should be discontinued. While it remains unclear why one opioid should produce nausea and vomiting and another does not, if nausea or vomiting persist, changing to a different equianalgesic opioid may reduce emetic side effects. A history of severe nausea with previous opioid treatment may prompt pretreating with antiemetic therapy. Once antiemetics are given, there is usually no need to discontinue the opioid.

Opioid-induced nausea and vomiting is thought to result from stimulation within the medullary chemoreceptor trigger zone (CTZ), a brainstem center responsible for afferent input to the emetic center. These anatomical areas are rich in neurotransmitter receptors that correspond to antiemetic agents used clinically and thus can guide therapeutic choices. These receptor systems relate to neurotransmitters and drugs such as histamine (H1) blockers and hydroxyzine, serotonin (5-HT-3) and ondansetron, dopamine (DA-2) and droperidol, or haloperidol, anticholinergics and scopolamine, and cholinergics and low-dose metoclopramide. It is not clear whether benzodiazepine-related antiemetic effects (such as those caused by lorazepam) are caused by direct action on benzodiazepine receptors found in the CTZ or indirect action on anxiety and psychological conditioning. Risk of opioid-related nausea may be increased if a patient is ambulatory, perhaps suggesting vestibular involvement. For patients complaining of nausea associated with movement, promethazine is effective and available for oral, rectal, and parenteral administration. There are many other causes of nausea and vomiting that can concomitantly occur with, but be unrelated to, opioids. These include: chemotherapy (particularly cisplatin), radiation therapy, metastases (particularly brain and gastrointestinal), increased intracranial pressure, ulcer disease, esophagitis, gastritis, electrolyte imbalance, acid-base disorder, uremia, liver disease, infection, pregnancy, fear, or anxiety. Since the single most effective antiemetic is not always predictable, we often choose the agent that offers secondary benefits such as promotility, sedative, antipuritic, and anxiolytic or antipsychotic properties.

Opioid-related sedation is common and can indicate either excess drug dose or even delirium. Opioid-induced sedation is usually temporary, resolving over time as patients accommodate to a new opioid drug, and this side effect typically responds well to dose reduction. It should not be confused with delirium as discussed in more detail in a later section. In those with significant sedation, the opioid dose should be reduced to the minimal level required for adequate analgesia. In some cases where sedation occurs late in treatment, medication or metabolites may be accumulating. If so, either increasing the dose interval or changing to a different agent without active metabolites, such as fentanyl, may reduce sedation. In cases involving sedation, consider other non-opioid causes of sedation (e.g., other sedating drugs, encephalopathy, hypoxia). For unremitting sedation that limits other required therapy, stimulants such as dextroamphetamine or caffeine can reduce sedation until accommodation occurs.

Pruritus is uncommon with oral opioids but a common side effect of parenterally administered opioids. Pruritus is found in the majority of patients treated with intrathecal and epidural opioids and frequently in those treated with intravenous or intramuscular opioids. Such effects often vary with dose. Usually parenteral opioids produce mild pruritus, but moderate to severe pruritus does occur infrequently. Fortunately, tolerance usually occurs quickly. Opioid-related pruritus is often localized to the face, or less often the perineum, but can become generalized. The mechanism of opioid-induced pruritus is not well understood. Suggested hypotheses include μ-receptor stimulation, 5-hydroxytryptamine-3 receptor stimulation, histamine release, local excitation of posterior horn neurons, and central migration of spinal opioids to “itch centers” in the brain.

Opioid-induced pruritus may respond to a change of opioid agents. Naloxone is effective for opioid-related pruritus from any route of administration, and used at dosages that should not interfere with analgesia (1 μg/kg IVP every 10 minutes as needed: hold for decreased analgesia). Recent studies suggest prophylaxis with nalmefene 15 μg administered intravenously at the end of surgery. It reduces the incidence of itching and nausea associated with intravenous morphine administered by a patient-controlled analgesia (PCA) pump. Antihistamines may be effective for opioid-related pruritus, except when pruritus is due to spinal opioids.

Since non-sedating antihistamines are less effective than sedating antihistamines, the antipruritic efficacy of antihistamine therapy may, in part, be related to sedation. When sedation is to be avoided, recent studies have shown that intravenous ondansetron 8 mg effectively reduces epidural morphine-induced pruritis for 5 to 7 hours. Propofol, in small dosages (10 mg intravenous push), is also effective for controlling some cases of pruritus due to spinal opioids. At low doses, adverse effects from propofol should be minimal.

Depressed respiration is one of the most feared opioid-related side effects. Tolerance to opioid-related respiratory depression occurs early in chronic therapy. Depression of respiratory drive may occur more rapidly when oral or intravenous opioids are combined with epidural or intrathecal opioids and their combined use should be avoided. Prevention of respiratory depression is the key. One can reduce the risk of respiratory depression significantly by looking for factors predisposing a patient to respiratory depression such as increased age, history of sleep apnea, chronic obstructive pulmonary disease, and hepatic dysfunction. For patients requiring opiate analgesics at risk for respiratory depression, one simple way to provide analgesia involves calculating the required opiate dose to decrease pain, dividing the dose by 3, and giving one third of the calculated dose until adequate analgesia or side effects occur. For example, a 60-kg woman getting 0.1 mg/kg morphine intravenously would get 2 mg of intravenous morphine every 15 minutes as needed up to 6 mg, instead of getting all 6 mg of morphine intravenously at one time. Significant acute respiratory depression can be managed with the opiate-receptor antagonist naloxone. Dosages of naloxone for treating respiratory depression are as follows: 0.1 mg intravenous push repeated every 10 to 15 minutes as needed (1/4 of the usual 0.4-mg ampule of naloxone). Although naloxone may provide a brisk response, its duration of action is short and may require frequent dosing or continuous intravenous drip. Particular care must be given to the patient taking prolonged opioids because rapid administration of naloxone can precipitate withdrawal. In special cases, reversal of opioid actions can promote pulmonary edema. This effect is likely the result of reversal of opioid-induced pulmonary vascular smooth muscle relaxation. However, this is unusual unless the patient is predisposed toward pulmonary edema (congestive heart failure, adult respiratory distress syndrome, and so forth).

Signs that a patient may be developing tolerance include a fixed dose of opioid, resulting in decreasing analgesia or increasing dosages being required to maintain a stable effect. Just like tolerance to analgesia, tolerance may also occur due to opioid side effects (i.e., nausea, pruritis) developing at different rates for different side effects. Pain in the tolerant patient can usually be treated either by changing the opioid or increasing the dose. A patient who has become tolerant to one opioid drug may respond with ample analgesia to another opioid, suggesting that cross-tolerance between these drugs may be incomplete. Owing to incomplete cross-tolerance, equianalgesic dosages are not applicable in the opioid-tolerant patient. When starting a new opioid agent in a tolerant patient, the recommended starting dose is 50% less than the equianalgesic dose and is titrated to effective analgesia. There is evidence that NMDA-receptor blockade may attenuate tolerance; however, this is not clearly established with clinically relevant drugs. Dextromethorphan has recently been used for such purposes, but at present its effective dose or clinical efficacy are not clear.

Attempts to avoid dependency may lead to inadequate opioid dosages and undertreatment of pain. Understanding this state can help preserve the effective and humane use of opioids. Physical dependence is a pharmacologic property of opioids, implying that continuous exposure to a drug is necessary to avoid the withdrawal syndrome. Dependence reflects a biochemical adaptation from chronic exposure to opioids. Opioids inhibit cyclic adenosine monophosphate (cAMP). Sudden discontinuation of opioids or administration of an opioid antagonist can induce a rebound disinhibition of cAMP associated with symptoms of withdrawal. Physical dependence may be produced by little opiate exposure and may persist well beyond drug cessation.

Withdrawal usually occurs in a systematic progression. The least severe withdrawal symptoms typically appear earlier than the most severe. Withdrawal begins with increased irritability, restlessness, anxiety, insomnia, yawning, sweating, rhinorrhea, and lacrimation and later progresses to dilated pupils, gooseflesh, tremor, chills, anorexia, muscle cramps, nausea, vomiting, abdominal pain, diarrhea, agitation, fever, tachycardia, and other features of heightened sympathetic activity. Laboratory data may reveal leukocytosis, ketosis, metabolic acidosis or respiratory alkalosis, and electrolyte imbalance.

The withdrawal syndrome may be seen with discontinuation or antagonism of any opioid. However, sudden discontinuation of shorter acting opioids such as morphine or hydromorphone is more likely to produce withdrawal symptoms than longer acting agents such as methadone or transdermally administered fentanyl. Slow, systematic tapering of opioids at a daily rate of 15% to 20% can usually prevent the withdrawal state. Once it occurs, it may be reversed by reintroducing the opioid at dosages of 25% to 40% of the previous daily dose. Weaning bedtime doses last may help avoid sleep disturbances that are often associated with opioid cessation. Physical symptoms of sympathetic hyperactivity may be treated with sympatholytics. Effective sympatholytics include clonidine and beta blockers, although such agents can produce hypotension. Clonidine may produce sedation and its anti-withdrawal effects may be antagonized by tricyclic antidepressants.

When abrupt discontinuation of a chronic opioid is mandatory, clonidine detoxification can effectively blunt objective findings of sympathetic hyperactivity. It remains controversial whether clonidine may increase or mask subjective symptoms of withdrawal such as anxiety, insomnia, and restlessness. Such treatment often is begun at dosages of 10 to 20 μg/kg/day in 3 divided doses with subsequent adjustments to reduce signs of withdrawal while limiting hypotension. Clonidine may be maintained for 4 days for short-acting opioids and for 14 days for long-acting opioids. Tapering of clonidine can then occur over 4 to 6 days. Recently, there is increased interest in rapid opioid detoxification with intravenous naloxone and general anesthesia. Such treatment offers rapid effects but is of unproven long-term value.

Delirium is associated with fluctuating mental status and often has features of disorientation and agitation. Opioid-induced delirium is rarely due solely to an opioid and is usually multifactorial. If sedation is a prominent feature, its fluctuating pattern distinguishes it from simple drug-related sedation. Delirium induced by many various factors is thought to have an incidence in hospitalized patients of 25% to 50%, with a mortality rate of 10% to 65%.

Prominent signs of delirium include acute onset, fluctuating course, inattention, disordered thinking or speech, and altered level of consciousness. Level of consciousness is defined as “alert,” which corresponds to a normal level of consciousness, “vigilant,” which corresponds to a hyperalert level, “lethargy,” which corresponds to a drowsy or easily arousable level, “stupor,” which corresponds to a difficult to arouse level, and “coma,” which corresponds to an unarousable level. The condition may include perceptual disorders such as illusions, hallucinations, sleep disorders, and abnormal psychomotor activity, which may be either increased or decreased. Life-threatening causes of delirium include Wernike’s encephalopathy (thiamine deficiency: nystagmus, ophthalmoplegia, ataxia, confusion), hypoxia, hypertensive crisis, hypoperfusion states, anemia or bleeding, electrolyte imbalance (hyponatremia, hypercalcemia, hypokalemia), intracranial bleeding, edema or closed head trauma, meningitis, poisons or other drug toxicities, and withdrawal states such as from benzodiazepines. The list of medications associated with delirium is too long for this brief discussion. Drugs with anticholinergic side effects (such as found in drugs that are often co-prescribed with opioids such as tricyclic antidepressants) are among the drugs that most commonly cause delirium. Another common culprit is the class of benzodiazepine drugs. If opioids are suspected as the cause of delirium, a thorough investigation to rule out other possible causes should nonetheless be undertaken, as opioids are often incorrectly blamed for causing delirium. Treating the symptoms of delirium such as agitation or unpleasant hallucinations require use of neuroleptics. The most appropriate choice of neuroleptics is those with the least anticholinergic side effects, such as intravenous dosages of haldoperidol.