Opioids are useful agents for managing acute and chronic pain.¹ When prescribing these medications, an understanding of the risks and benefits is essential. Many organizations, including the American Pain Society and the American Academy of Pain Management, have educational materials and other resources available for physicians.^1,2 In addition, the European Association of Palliative Care (EAPC) Research Network has developed recommendations for treating opioid-induced adverse effects.³

The development of adverse effects from opioids may cause physicians to weigh the treatment risks against the benefits. Anticipating potential adverse effects in relation to predisposing patient factors is critical when addressing this problem. The mechanisms by which opioids cause these adverse effects are not always completely understood.

Sex, race, and increasing age are all factors shown to influence the development of adverse effects.⁴ Reductions in renal function associated with aging may lead to accumulation of opioids and their metabolites.⁵ To reduce the risk of developing adverse effects, downward dose adjustments or prolonging the opioid interval should be anticipated for persons older than 70 years.^1,5 Nausea and vomiting are less likely to occur in men than in women and are less likely in whites than in blacks.^4,6 The EAPC working group identified four general approaches to consider when encountering adverse effects caused by opioids: dose reduction of systemic opioid, symptomatic management of the adverse effect, opioid rotation, and switching the route of systemic administration.³

If pain is well controlled, small reductions in the dose of opioid may help resolve the adverse effect while maintaining pain control.³ Addition of nonopioid analgesics, use of adjuvant agents (e.g., tricyclic antidepressants), or treatments directed toward the source of pain are all options for providing a synergistic approach to pain management.³

Opioids have subtle differences in binding to the mu, kappa, and sigma receptors; the clinical effects can vary from one agent to another.^7,8 Opioid rotation is a concept in which one opioid is exchanged for another to improve pain control or manage certain adverse effects. Pain experts support the clinical use of opioid rotation as a reasonable strategy.^8–10 Patient response to opioid therapies can be highly variable, so physicians should be knowledgeable about different opioids and also understand the fundamentals of proper equianalgesic conversion.

A MEDLINE search (1966–2005) was performed to identify evidence-based approaches for managing opioid-induced adverse effects. In addition, evaluation of consensus guidelines and various working groups providing expert opinion were used in developing this review. Few randomized comparative studies have evaluated the safety and effectiveness of various treatment regimens to manage adverse effects of opioids. Many of the recommendations for management are based on consensus opinion and clinical experience.

Nausea

Nausea has been reported to occur in approximately 25 percent of patients treated with opioids; prophylactic measures generally are not required at the initiation of therapy.^4,11 Mechanisms for nausea may include direct stimulation of the chemoreceptor trigger zone (CTZ), reduced gastrointestinal motility, or enhanced vestibular sensitivity.^7,12,13 An understanding of these mechanisms will aid physicians in the selection of antiemetic agents to target the underlying cause. Nausea that results from opioids usually is transient; however, treatment should be made available if substantial nausea and vomiting develop.¹³

The initial antiemetic choice will depend on patient characteristics including concomitant disease states and likelihood of adverse reactions or drug interactions. Available options include antipsychotics, metoclopramide (Reglan), serotonin antagonists, antihistamines, and corticosteroids. These agents are used alone or in combination. There is no proven clinical benefit of one antiemetic over another.³ An understanding of the potential mechanism for the opioid-induced nausea should factor into selection.

Antipsychotics are inexpensive agents that block dopamine receptors within the CTZ.¹⁴ Haloperidol (Haldol) and prochlorperazine (Compazine) are considered first-line options, primarily based on expert opinion.^3,10 Adverse effects such as akathisia, dystonic reactions, sedation, and orthostatic hypotension may occur with antipsychotic use. Another option is metoclopramide, which will block dopamine receptors in the CTZ and promote peristalsis through enhanced release of acetylcholine.¹⁵ Central nervous system (CNS) effects (e.g., sedation and extrapyramidal effects) often limit the use of metoclopramide.

Serotonin antagonists block serotonin release, primarily within the gastrointestinal tract, but they have secondary effects on blocking serotonin centrally.¹⁵ These agents are more useful in preventing nausea resulting from highly emetogenic chemotherapy, radiation, and postoperative sickness.¹⁶ Although they are free of extrapyramidal adverse effects, routine use of serotonin antagonists in managing opioid-induced nausea often is cost prohibitive. Because of this, these products typically are not considered first-line agents, although they are possible alternatives when other products are ineffective or not well tolerated.¹⁶

Antihistamines and anticholinergic agents reduce opioid-induced vestibular sensitivity. Patients experiencing nausea related to ambulation are most likely to benefit from medications that antagonize the effects of acetylcholine and histamine.¹⁷ The use of these medications often is limited by sedation and orthostatic changes. Corticosteroids have an unclear mechanism of action for treating nausea caused by opioids. Jitteriness, confusion, and increased appetite are adverse effects that need to be considered before starting corticosteroids. An overview of agents used for treating nausea and vomiting is listed in Table 1.^14–16

Constipation

Constipation is the most common adverse effect occurring with chronic opioid use. Prophylactic treatments are essential to minimize this complication. Opioids have various effects on the gastrointestinal tract, including decreases in motility, secretions, and blood flow, which lead to hard, dry feces.^18–20 The constipating effects of opioids are considered to be dose-related, and tolerance to this symptom rarely develops. A common goal of therapy is for patients to have one bowel movement every one to two days.¹⁹

Nondrug treatments, such as increasing fluid and dietary fiber intake, increasing physical activity, and establishing a toileting routine, should be implemented to minimize the risk of constipation.²¹ Monotherapy with stool softeners is considered ineffective, and use of a scheduled stimulant laxative often is required.¹ There are no studies showing superiority of one laxative over another. However, one common approach is the scheduled use of senna with or without a stool softener.^1,3 If patients do not have an adequate response, a trial of an osmotic agent (e.g., sorbitol) may be used. Bulk-forming laxatives also are an option, although these agents require adequate fluid intake that may not be appropriate in all patient populations.¹⁹ Periodic use of saline laxatives or administration of suppositories or enemas may be needed.

Transdermal fentanyl (Duragesic) is considered an option for patients who have difficulty with the constipating effects of oral opioids. Although not free of constipating adverse effects, transdermal fentanyl has been shown to have fewer such effects compared with various oral opioids.^21–23 A retrospective cohort study found a significantly higher risk of developing constipation with oral oxycodone (Roxicodone) compared with transdermal fentanyl.²² A randomized crossover trial found a significant reduction in constipation in the transdermal fentanyl group compared with sustained-release oral morphine (29 and 48 percent, respectively).²³ Table 2^19,24 lists selected agents used to treat constipation.

One concept to reduce the adverse effects of opioids is the use of very small doses of opioid antagonists.^25–28 The rationale is that agents such as naloxone (Narcan) have a biphasic effect whereby very low doses reduce the incidence of opioid adverse effects and may augment the analgesic effect.^25,28 Much of the data are limited to the inpatient setting with intravenous administration of the opioid antagonist.^25–27 Concomitant administration of intravenous naloxone with morphine infusions has been studied, but the results have been mixed.^25–27 More research is needed before this treatment is implemented as part of routine practice.

CNS Adverse Effects

Sedation and decreased cognition are examples of CNS adverse effects associated with opioid use. Most of the these effects are transient, although some patients require additional therapy to help cope with the unwanted effects. An initial step is to identify and eliminate unnecessary medications that may worsen underlying sedation or cognitive function.

The reported incidence of sedation is between 20 and 60 percent.³ It commonly presents with initiation of opioid therapy or with dose increases.⁷ Pharmacologic management of sedation through the use of psychostimulants (e.g., methylphenidate [Ritalin]) may be considered, although data supporting their use are lacking in clinical trials.^1,29 In addition, potential side effects of psychostimulants warrant judicious prescribing in this setting.

Cognitive changes may present, especially in patients who have cognitive dysfunction at baseline. Similar to sedation, this adverse effect appears to be related to initiation of an opioid or dose increases.³⁰ Persistent confusion often is compounded in the presence of infection, dehydration, metabolic abnormalities, or advanced cancer.³¹ Treatment of cognitive impairment may involve the use of antipsychotics, with most of the evidence based on clinical experience in managing delirium in medically ill patients.³ A recent Cochrane review evaluated the use of medications for treating terminally ill patients with delirium.³² Only one study of terminal patients with acquired immunodeficiency syndrome met the criteria for the Cochrane review.³³ Haloperidol and chlorpromazine (Thorazine) were found to be effective in treating delirium in this population.^32,33 Low doses of haloperidol often are used first because of its effectiveness and low incidence of cardiovascular and anticholinergic effects.^3,10,31

Benzodiazepines have been used with antipsychotics when severe agitation is present.³ Although they may be used as adjunctive therapy, benzodiazepines could enhance the sedative effects and perhaps worsen cognition.³²

An emerging concept is the use of acetylcholinesterase inhibitors for managing sedation and delirium associated with opioids. Theoretically, depression of central cholinergic activity is mediated partially through opioid use.³⁴ There is limited evidence supporting the use of donepezil (Aricept) for managing opioid-induced sedation and delirium.³⁵ Table 3^10,14 highlights medications used to treat the cognitive adverse effects of opioids.

Pruritus

The likelihood of developing pruritus with opioid use ranges from 2 to 10 percent.³ The probability is increased when opioids are given by epidural or intraspinal injections.³⁶ The postulated mechanism of pruritus is related to histamine release in the periphery or to a centrally mediated process. The pruritus associated with opioids most likely is an adverse effect rather than an allergic reaction.⁷

Prospective studies evaluating medications to treat opioid-induced pruritus are lacking. Antihistamines (e.g., diphenhydramine [Benadryl]) often are used to manage this symptom. Opioid rotation, dose reduction, or nondrug treatments such as cool compresses or moisturizers may be necessary for certain patients.⁷ One case series has identified paroxetine (Paxil) as a possible treatment for pruritus in opioid-treated patients with cancer.³⁷ An overview is provided in Table 4.³⁸