Am Fam Physician. 2006;74(8):1347-1354
Author disclosure: nothing to disclose.
Opioid analgesics are useful agents for treating pain of various etiologies; however, adverse effects are potential limitations to their use. Strategies to minimize adverse effects of opioids include dose reduction, symptomatic management, opioid rotation, and changing the route of administration. Nausea occurs in approximately 25 percent of patients; prophylactic measures may not be required. Patients who do develop nausea will require antiemetic treatment with an anti-psychotic, prokinetic agent, or serotonin antagonist. Understanding the mechanism for opioid-induced nausea will aid in the selection of appropriate agents. Constipation is considered an expected side effect with chronic opioid use. Physicians should minimize the development of constipation using prophylactic measures. Monotherapy with stool softeners often is not effective; a stool softener combined with a stimulant laxative is preferred. Sedation and cognitive changes occur with initiation of therapy or dose escalation. Underlying disease states or other centrally acting medications often will compound the opioid’s adverse effects. Minimizing unnecessary medications and judicious use of stimulants and antipsychotics are used to manage the central nervous system side effects. Pruritus may develop, but it is generally not considered an allergic reaction. Antihistamines are the preferred management option should pharmacotherapy treatment be required.
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
|Clinical recommendation||Evidence rating||References|
|Opioid rotation may be used for managing opioid-induced adverse effects.||C||8,9|
|Because no antiemetic has been shown to be superior to another in this setting, cost can be used to determine the treatment method of opioid-induced nausea.||C||3,16|
|Monotherapy with stool softeners for constipation is not recommended.||C||1|
|Transdermal fentanyl (Duragesic) is an option for pain control in patients with constipation from oral opioids.||B||21–23|
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 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
|Classification||Medication and adult dose||Cost*||Comments|
|Antihistamines||Diphenhydramine (Benadryl) 25 to 50 mg orally or IV every four to six hours||Oral: $0.16 to $0.24 (generic) or $0.69 to $1.05 (brand) per day||These agents more useful if nausea related to ambulation|
|IV: $1.86 per 50-mg vial (brand)|
|Meclizine (Antivert) 12.5 to 25 mg orally every six to eight hours||Oral: $0.12 to $1.05 (generic) or $1.58 to $3.35 (brand) per day|
|Antipsychotics and related agents||Haloperidol (Haldol) 0.5 to 2 mg orally two to four times per day||Oral: $0.50 to $2.05 per day||Reasonable agent for treating nausea; multiple uses for haloperidol in palliative medicine|
|Prochlorperazine (Compazine) 5 to 10 mg oral or IV every six to eight hours or 25 mg rectally every 12 hours||Oral: $2.67 to $3.24 (generic) or $3.21 to $4.28 (brand) per day||Prochlorperazine less sedating than promethazine|
|IV: $6.70 per 10-mL vial|
|Suppository: $6.44 to $13.78 (generic) or $7.68 (brand) per day|
|Promethazine (Phenergan) 12.5 to 25 mg orally, IV, or rectally every four to six hours||Oral: $1.74 to $3.06 (generic) or 17.49 to $26.24 (brand) per day||Dopamine-blocking properties less than prochlorperazine; more antihistaminic qualities|
|IV: $2.29 (generic) or $2.97 (brand) per 25-mg vial|
|Suppository: $3.37 to $4.46 per dose|
|Prokinetic agents||Metoclopramide (Reglan) 5 to 10 mg orally or IV four times per day||Oral: $0.42 to $1.70 (generic) or $3.12 to $5.04 (brand) per day||Lower doses preferred in older patients; more useful if early satiety is the presenting problem|
|IV: $0.84 (generic) or $2.26 (brand) per 10-mg vial|
|Serotonin antagonists||Granisetron (Kytril) 1 mg orally or IV twice per day||Oral: $104.24 per day||Because of cost, this class best reserved for treatment failures; other serotonin antagonists also available|
|IV: $195.20 per 1-mg single-dose vial|
|Ondansetron (Zofran) 4 mg orally or IV two to four times per day||Oral: $48.47 to $96.94 per day|
|IV: $25.60 per 2-mg single-dose vial|
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 219,24 lists selected agents used to treat constipation.
|Laxative||Adult dose||Onset of action||Cost*||Comments|
|Methylcellulose (Citrucel)||Oral (powder or caplets): one to three times per day||12 to 48 hours||$0.38 to $0.51 per day||Source of fiber; less gas formation compared with psyllium|
|Polycarbophil (Fibercon)||Oral (caplets): one to four times per day||12 to 48 hours||$0.12 to $0.48 (generic) or $0.14 to $0.56 (brand) per day||May be ineffective if patient has pre-existing constipation or if patient is nonambulatory|
|Psyllium (Metamucil)||Oral (powder, wafer, or capsule): one to three times per day||12 to 48 hours||Powder: $4.25 (generic) for 371 g or $8.17 (brand) for 390 g||Source of fiber; adequate water ingestion required (1,000 to 1,500 mL per day)|
|Capsule: $0.09 to $0.27 per day|
|Wafer: $0.18 to $0.55 per day|
|Lactulose||Oral (liquid): 15 to 60 mL per day||24 to 48 hours||$10.51 to $32.40 per 480-mL bottle||More expensive than sorbitol|
|Polyethylene glycol (Miralax)||Oral (powder): 17 g (i.e., one capful) in 8 oz water daily||24 to 48 hours||$2.11 per day||Lacks salty taste, making it a good option; more expensive than sorbitol|
|Sorbitol||Oral (liquid): 15 to 60 mL per day||24 to 48 hours||$7.23 to $7.57 per 480-mL bottle||70% solution; sweet taste|
|Magnesium citrate (Citroma)||Oral (liquid): 8 oz orally once; may repeat as needed||0.5 to 3 hours||$1.49 per 300-mL bottle||Saline laxatives more useful on an as-needed basis; electrolyte imbalances are possible with all of the saline laxatives; use caution when prescribing to patients with declining renal function|
|Magnesium hydroxide (Milk of Magnesia)||Oral (liquid): 15 to 60 mL once; may repeat as needed||0.5 to 3 hours||$3.05 (generic) or $3.53 (brand) per 360-mL bottle|
|Sodium phosphate (Phospho-Soda)||Rectal: one adult enema||Within 30 minutes||$0.80 per bottle|
|Bisacodyl (Dulcolax)||Oral: 10 to 15 mg one to three times per day||Oral: 6 to 12 hours||Oral: $0.13 to $0.49 (generic) or $0.40 to $1.20 (brand) per day||Not often used for opioid-induced constipation|
|Rectal: one suppository (10 mg) per day||Rectal: 15 to 60 minutes||Rectal: $0.24 (generic) or $0.86 (brand) per suppository|
|Senna||Oral (liquid or tablet): two tablets once per day to four tablets twice per day||6 to 12 hours||$0.20 to $3.50 per day||Good first-line choice in those receiving chronic opioids|
|Docusate sodium (Colace)||Oral (capsule or liquid): 100 to 400 mg once or twice per day||24 to 72 hours||$0.03 to $0.28 (generic) or $0.26 to $0.52 (brand) per day||Not effective as monotherapy for opioid-induced constipation; often used in combination with other laxatives|
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
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 310,14 highlights medications used to treat the cognitive adverse effects of opioids.
|Delirium or reduced cognition||Haloperidol (Haldol) 0.5 to 2 mg orally twice per day||$0.50 to $2.05 per day||Often first choice; inexpensive; minimal sedation and cardiovascular effects|
|Quetiapine (Seroquel) 25 to 50 mg orally twice per day||$4.08 to $8.16 per day||More sedating than haloperidol|
|Risperidone (Risperdal) 0.25 to 1 mg orally twice per day||$6.94 to $8.10 per day||Other antipsychotics also are available options.|
|Sedation||Dextroamphetamine (Dexedrine) 2.5 to 5 mg orally twice per day||$0.27 to $0.54 (generic) or $0.52 to $1.04 (brand) per day||Judicious use advised; adverse effects include tremor, delirium, decreased appetite, and hallucinations.|
|Methylphenidate (Ritalin) 2.5 to 5 mg orally twice per day||$0.30 to $0.84 (generic) or $0.63 to $1.26 (brand) per day|
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
|Cetirizine (Zyrtec) 10 mg orally once per day||$2.33 per day|
|Diphenhydramine (Benadryl) 25 to 50 mg orally every four to six hours||$0.16 to $0.24 (generic) or $0.69 to $1.05 (brand) per day|
|Fexofenadine (Allegra) 60 mg orally twice per day||$3.45 per day|
|Hydroxyzine (Atarax) 25 to 100 mg orally at bedtime as needed||$0.60 to $2.93 per day|
|Loratadine (Claritin) 10 mg orally once per day||$1.02 per day|