Management of Common Opioid-Induced
Adverse Effects
JOHN M. SWEGLE, PHARM.D., Mercy Family Medicine Residency Program, Mason City, Iowa
CRAIG LOGEMANN, PHARM.D., Urbandale Family Physicians, Urbandale, Iowa
Opioid analgesics are useful agents for treating pain of various etiologies; however, adverse effects are potential limita-
tions 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; pro-
phylactic 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. Physi-
cians 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 treat-
ment be required. (Am Fam Physician 2006;74:1347-54. Copyright 2006 American Academy of Family Physicians.)

Opioids are useful agents for man- persons older than 70 years.1,5 Nausea and aging acute and chronic pain.1 vomiting are less likely to occur in men than When prescribing these medi- in women and are less likely in whites than cations, an understanding of in blacks.4,6 The EAPC working group iden- the risks and benefits is essential. Many tified four general approaches to consider organizations, including the American Pain when encountering adverse effects caused by Society and the American Academy of Pain opioids: dose reduction of systemic opioid, Management, have educational materials and symptomatic management of the adverse other resources available for physicians.1,2 effect, opioid rotation, and switching the In addition, the European Association of route of systemic administration.3Palliative Care (EAPC) Research Network If pain is well controlled, small reductions has developed recommendations for treating in the dose of opioid may help resolve the opioid-induced adverse effects.3 adverse effect while maintaining pain con- The development of adverse effects from trol.3 Addition of nonopioid analgesics, use opioids may cause physicians to weigh the of adjuvant agents (e.g., tricyclic antidepres-treatment risks against the benefits. Antici- sants), or treatments directed toward the pating potential adverse effects in relation to source of pain are all options for providing a predisposing patient factors is critical when synergistic approach to pain management.3addressing this problem. The mechanisms by Opioids have subtle differences in binding which opioids cause these adverse effects are to the mu, kappa, and sigma receptors; the not always completely understood.
clinical effects can vary from one agent to Sex, race, and increasing age are all fac- another.7,8 Opioid rotation is a concept in tors shown to influence the development of which one opioid is exchanged for another adverse effects.4 Reductions in renal function to improve pain control or manage certain associated with aging may lead to accumula- adverse effects. Pain experts support the tion of opioids and their metabolites.5 To clinical use of opioid rotation as a reasonable reduce the risk of developing adverse effects, strategy.8-10 Patient response to opioid thera-downward dose adjustments or prolonging pies can be highly variable, so physicians the opioid interval should be anticipated for should be knowledgeable about different Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2006 American Academy of Family Physicians. For the private, noncommercial use of one individual user of the Web site. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests.
Opioid-Induced Adverse Effects
Opioid rotation may be used for managing opioid-induced adverse effects.
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.
Monotherapy with stool softeners for constipation is not recommended.
Transdermal fentanyl (Duragesic) is an option for pain control in patients A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evi-dence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page 1263 or http://www.aafp.org/afpsort.xml. opioids and also understand the fundamen- tals of proper equianalgesic conversion.
(Reglan), serotonin antagonists, antihista- A MEDLINE search (1966-2005) was mines, and corticosteroids. These agents are performed to identify evidence-based used alone or in combination. There is no approaches for managing opioid-induced proven clinical benefit of one antiemetic over adverse effects. In addition, evaluation of another.3 An understanding of the potential consensus guidelines and various working mechanism for the opioid-induced nausea groups providing expert opinion were used should factor into selection.
in developing this review. Few random- Antipsychotics are inexpensive agents that ized comparative studies have evaluated the block dopamine receptors within the CTZ.14 safety and effectiveness of various treat- ment regimens to manage adverse effects of zine (Compazine) are considered first-line opioids. Many of the recommendations for options, primarily based on expert opin-management are based on consensus opin- ion.3,10 Adverse effects such as akathisia, dystonic reactions, sedation, and orthostatic hypotension may occur with antipsychotic Nausea has been reported to occur in approx- imately 25 percent of patients treated with the CTZ and promote peristalsis through opioids; prophylactic measures generally are enhanced release of acetylcholine.15 Central not required at the initiation of therapy.4,11 nervous system (CNS) effects (e.g., sedation Mechanisms for nausea may include direct and extrapyramidal effects) often limit the stimulation of the chemoreceptor trigger use of metoclopramide.
zone (CTZ), reduced gastrointestinal motil- ity, or enhanced vestibular sensitivity.7,12,13 release, primarily within the gastrointesti-An understanding of these mechanisms will nal tract, but they have secondary effects on aid physicians in the selection of antiemetic blocking serotonin centrally.15 These agents agents to target the underlying cause. Nausea are more useful in preventing nausea result-that results from opioids usually is transient; ing from highly emetogenic chemotherapy, however, treatment should be made available radiation, and postoperative sickness.16 if substantial nausea and vomiting develop.13 Although they are free of extrapyramidal The initial antiemetic choice will depend on adverse effects, routine use of serotonin patient characteristics including concomitant antagonists in managing opioid-induced nau-disease states and likelihood of adverse reac- sea often is cost prohibitive. Because of this, tions or drug interactions. Available options these products typically are not considered 1348  American Family Physician
Volume 74, Number 8October 15, 2006 Opioid-Induced Adverse Effects
first-line agents, although they are possible for treating nausea caused by opioids. Jit-alternatives when other products are ineffec- teriness, confusion, and increased appetite are adverse effects that need to be considered Antihistamines and anticholinergic agents before starting corticosteroids. An overview reduce opioid-induced vestibular sensitiv- of agents used for treating nausea and vom- ity. Patients experiencing nausea related to iting is listed in Table 1.14-16
ambulation are most likely to benefit from
medications that antagonize the effects of CONsTIPATION
acetylcholine and histamine.17 The use of Constipation is the most common adverse
these medications often is limited by seda-
effect occurring with chronic opioid use. tion and orthostatic changes. Corticoste- Prophylactic treatments are essential to mini- roids have an unclear mechanism of action mize this complication. Opioids have various TABLE 1
selected Medications for Treating Opioid-Induced Nausea
best reserved for treatment failures; other serotonin *—Estimated cost to the pharmacist based on average wholesale cost in Red Book, Montvale, N.J.: Medical Economics Data, 2006. Cost to patient will be higher, depending on prescription fil ing fee. Information from references 14 through 16. October 15, 2006Volume 74, Number 8 American Family Physician  1349
Opioid-Induced Adverse Effects
effects on the gastrointestinal tract, including have a biphasic effect whereby very low decreases in motility, secretions, and blood doses reduce the incidence of opioid adverse flow, which lead to hard, dry feces.18-20 The effects and may augment the analgesic constipating effects of opioids are consid- effect.25,28 Much of the data are limited ered to be dose-related, and tolerance to this to the inpatient setting with intravenous symptom rarely develops. A common goal administration of the opioid antagonist.25-of therapy is for patients to have one bowel 27 Concomitant administration of intrave-movement every one to two days.19 Nondrug treatments, such as increasing has been studied, but the results have been fluid and dietary fiber intake, increasing mixed.25-27 More research is needed before
physical activity, and establishing a toileting this treatment is implemented as part of
routine, should be implemented to minimize routine practice.
the risk of constipation.21 Monotherapy with
stool softeners is considered ineffective, and CNs ADVERsE EFFECTs
use of a scheduled stimulant laxative often Sedation and decreased cognition are exam-
is required.1 There are no studies showing ples of CNS adverse effects associated with
superiority of one laxative over opioid use. Most of the these effects are another. However, one com- transient, although some patients require Constipation is the most 
mon approach is the scheduled additional therapy to help cope with the common adverse effect 
use of senna with or without a unwanted effects. An initial step is to iden- occurring with chronic  
stool softener.1,3 If patients do tify and eliminate unnecessary medications opioid use.
not have an adequate response, that may worsen underlying sedation or a trial of an osmotic agent cognitive function.
(e.g., sorbitol) may be used. Bulk-forming laxatives also are an option, although these between 20 and 60 percent.3 It commonly agents require adequate fluid intake that presents with initiation of opioid therapy or may not be appropriate in all patient popu- lations.19 Periodic use of saline laxatives or agement of sedation through the use of administration of suppositories or enemas psychostimulants (e.g., methylphenidate may be needed.
[Ritalin]) may be considered, although data supporting their use are lacking in clinical sidered an option for patients who have dif- trials.1,29 In addition, potential side effects ficulty with the constipating effects of oral of psychostimulants warrant judicious pre-opioids. Although not free of constipating scribing in this setting.
adverse effects, transdermal fentanyl has been shown to have fewer such effects com- cially in patients who have cognitive dys- pared with various oral opioids.21-23 A retro- function at baseline. Similar to sedation, spective cohort study found a significantly this adverse effect appears to be related to higher risk of developing constipation with initiation of an opioid or dose increases.30 oral oxycodone (Roxicodone) compared Persistent confusion often is compounded with transdermal fentanyl.22 A randomized in the presence of infection, dehydration, crossover trial found a significant reduction metabolic abnormalities, or advanced can-in constipation in the transdermal fentanyl cer.31 Treatment of cognitive impairment group compared with sustained-release may involve the use of antipsychotics, oral morphine (29 and 48 percent, respec- with most of the evidence based on clini- tively).23 Table 219,24 lists selected agents used cal experience in managing delirium in to treat constipation.
medically ill patients.3 A recent Cochrane One concept to reduce the adverse effects review evaluated the use of medications of opioids is the use of very small doses for treating terminally ill patients with of opioid antagonists.25-28 The rationale delirium.32 Only one study of terminal is that agents such as naloxone (Narcan) patients with acquired immunodeficiency 1350  American Family Physician
Volume 74, Number 8October 15, 2006 Opioid-Induced Adverse Effects
selected Medications for Treating Opioid-Induced Constipation
$0.12 to $0.48 (generic) May be ineffective if patient has imbalances are possible with all of the saline laxatives; use caution when prescribing to patients with declining renal function stimulant
stool softener
often used in combination with other laxatives *—Estimated cost to the pharmacist based on average wholesale cost in Red Book, Montvale, N.J.: Medical Economics Data, 2006. Cost to patient will be higher, depending on prescription fil ing fee. Information from references 19 and 24. TABLE 3
selected Medications for Treating Opioid-Induced  
Central Nervous system symptoms
delirium, decreased appetite, and hal ucinations.
*—Estimated cost to the pharmacist based on average wholesale cost in Red Book, Montvale, N.J.: Medical Economics Data, 2006. Cost to patient will be higher, depending on prescription fil ing fee. Information from references 10 and 14. syndrome met the criteria for the Cochrane incidence of cardiovascular and anticholin-review.33 Haloperidol and chlorpromazine ergic effects.3,10,31(Thorazine) were found to be effective in treating delirium in this population.32,33 antipsychotics when severe agitation is pres-Low doses of haloperidol often are used ent.3 Although they may be used as adjunc-first because of its effectiveness and low tive therapy, benzodiazepines could enhance the sedative effects and perhaps worsen cognition.32 tylcholinesterase inhibitors for managing selected Medications for Treating Opioid-Induced Pruritus
sedation and delirium associated with opi-oids. Theoretically, depression of central cholinergic activity is mediated partially Antihistamines
through opioid use.34 There is limited evi- dence supporting the use of donepezil (Ari- cept) for managing opioid-induced sedation and delirium.35 Table 310,14 highlights medi- cations used to treat the cognitive adverse 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 *—Estimated cost to the pharmacist based on average wholesale cost in Red Book, postulated mechanism of pruritus is related Montvale, N.J.: Medical Economics Data, 2006. Cost to patient will be higher, depending on prescription fil ing fee. to histamine release in the periphery or to a †—This is not an al -inclusive list. Any antihistamine can be used. centrally mediated process. The pruritus asso- ciated with opioids most likely is an adverse effect rather than an allergic reaction.7 1352  American Family Physician
Volume 74, Number 8October 15, 2006 Opioid-Induced Adverse Effects
6. Pleym H, Spigset O, Kharasch ED, Dale O. Gender dif- tions to treat opioid-induced pruritus are ferences in drug effects: implications for anesthesiolo-gists. Acta Anaesthesiol Scand 2003;47:241-59.
lacking. Antihistamines (e.g., diphenhydr- 7. McNicol E, Horowicz-Mehler N, Fisk RA, Bennett K, Gialeli-Goudas M, Chew PW, et al. Management of opioid side effects in cancer-related and chronic noncancer pain: a systematic review. J Pain 2003;4: reduction, or nondrug treatments such as cool compresses or moisturizers may be 8. Mercadante S. Opioid rotation for cancer pain: ratio-necessary for certain patients.7 One case nale and clinical aspects. Cancer 1999;86:1856-66.
series has identified paroxetine (Paxil) as a 9. de Stoutz ND, Bruera E, Suarez-Almazor M. Opioid rota-possible treatment for pruritus in opioid- tion for toxicity reduction in terminal cancer patients. J Pain Symptom Manage 1995;10:378-84.
treated patients with cancer.37 An overview 10. Hanks F, Cherny NI, Fal on M. Opioid analgesic therapy. In: Doyle D, Hanks G, Cherny N, Calman K, eds. Oxford Textbook of Pal iative Medicine. 3rd ed. New York, N.Y.: Oxford University Press, 2004:316-41.
The Authors
11. Meuser T, Pietruck C, Radbruch L, Stute P, Lehmann JOHN M. SWEGLE, PHARM.D., is a clinical pharmacist KA, Grond S. Symptoms during cancer pain treatment at Mercy Family Medicine Residency Program in Mason fol owing WHO-guidelines: a longitudinal fol ow-up City, Iowa, and assistant professor at the University study of symptom prevalence, severity and etiology. Pain 2001;93:247-57.
of Iowa Col ege of Pharmacy, Division of Clinical and Administrative Pharmacy, in Iowa City. Dr. Swegle received 12. Sussman G, Shurman J, Creed MR, Larsen LS, Fer- his doctor of pharmacy degree from the University of rer-Brechner T, Noll D, et al. Intravenous ondansetron Iowa. He completed a pharmacy residency and a family for the control of opioid-induced nausea and vomit-ing. International S3AA3013 Study Group. Clin Ther medicine residency at the University of Iowa Col ege of Pharmacy and the University of Iowa Hospitals and Clinics in Iowa City.
13. Flake ZA, Scal ey RG, Bailey AG. Practical selection of antiemetics. Am Fam Physician 2004;69:1169-74.
CRAIG LOGEMANN, PHARM.D., is a clinical pharmacist 14. Baldessarini RJ, Tarazi FI. Drugs and the treatment of at Urbandale (Iowa) Family Physicians and is an adjunct psychiatric disorders. In: Goodman LS, Hardman JG, associate professor at the University of Iowa Col ege Limbird LE, Gilman AG, eds. Goodman & Gilman’s the of Pharmacy, Division of Clinical and Administrative Pharmacologic Basis of Therapeutics. 10th ed. New Pharmacy. Dr. Logemann received his doctor of pharmacy York, N.Y.: McGraw-Hil , 2001:485-520.
degree from the University of Minnesota in Minneapolis 15. Pasricha PJ. Prokinetic agents, antiemetics, and agents and completed a pharmacy residency at the University of used in irritable bowel syndrome. In: Goodman LS, Hardman JG, Limbird LE, Gilman AG, eds. Goodman & Gilman’s the Pharmacologic Basis of Therapeutics. 10th Address correspondence to John Swegle, Pharm.D., ed. New York, N.Y.: McGraw-Hil , 2001:1021-36.
Mercy Family Medicine Residency Program, 1000 4th 16. Apfel CC, Korttila K, Abdal a M, Kerger H, Turan A, St. SW, Mason City, IA 50401-2859 (e-mail: john-swe- Veder I, et al. A factorial trial of six interventions for [email protected]). Reprints are not available from the the prevention of postoperative nausea and vomiting. Author disclosure: Nothing to disclose.
17. Ferris FD, Kerr IG, Sone M, Marcuzzi M. Transdermal scopolamine use in the control of narcotic-induced nausea. J Pain Symptom Manage 1991;6:389-93.
18. De Luca A, Coupar IM. Insights into opioid action in the intestinal tract. Pharmacol Ther 1996;69:103-15.
1. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 5th ed. Glenview, Il .: American 19. Pappagal o M. Incidence, prevalence, and management of opioid bowel dysfunction. Am J Surg 2001;182(5A 2. Bowsell MV, Cole BE, Weiner RS, American Academy of Pain Management. Weiner’s Pain Management: A 20. Herndon CM, Jackson KC II, Hallin PA. Manage- Practical Guide for Clinicians. 7th ed. Boca Raton, Fla.: ment of opioid-induced gastrointestinal effects in patients receiving palliative care. Pharmacotherapy 3. Cherny N, Ripamonti C, Pereira J, Davis C, Fal on M, McQuay H, et al. Strategies to manage the adverse 21. Canty SL. Constipation as a side effect of opioids. effects of oral morphine: an evidence-based report. 22. Staats PS, Markowitz J, Schein J. Incidence of consti- 4. Cepeda MS, Farrar JT, Baumgarten M, Boston R, Carr pation associated with long-acting opioid therapy: DB, Strom BL. Side effects of opioids during short-term a comparative study. South Med J 2004;97:129-34.
administration: effect of age, gender, and race. Clin 23. Al an L, Hays H, Jensen NH, de Waroux BL, Bolt M, Don- ald R, et al. Randomised crossover trial of transdermal 5. Forman WB. Opioid analgesic drugs in the elderly. Clin fentanyl and sustained release oral morphine for treat- ing chronic non-cancer pain. BMJ 2001;322:1154-8.
October 15, 2006Volume 74, Number 8 American Family Physician  1353
Opioid-Induced Adverse Effects
24. Jafri S, Pasricha PJ. Agents used for diarrhea, constipa- 31. Cherny NI. The management of cancer pain. CA Cancer tion, and inflammatory bowel disease; agents used for biliary and pancreatic disease. In: Goodman LS, 32. Jackson KC, Lipman AG. Drug therapy for delirium Hardman JG, Limbird LE, Gilman AG, eds. Goodman & in terminal y ill patients. Cochrane Database Syst Rev Gilman’s the Pharmacologic Basis of Therapeutics. 10th ed. New York, N.Y.: McGraw-Hil , 2001:1037-58.
33. Breitbart W, Marotta R, Platt MM, Weisman H, Der- 25. Gan TJ, Ginsberg B, Glass PS, Fortney J, Jhaveri R, evenco M, Grau C, et al. A double-blind trial of Perno R. Opioid-sparing effects of a low-dose infusion haloperidol, chlorpromazine, and lorazepam in the of naloxone in patient-administered morphine sulfate. treatment of delirium in hospitalized AIDS patients. Am 26. Sartain JB, Barry JJ, Richardson CA, Branagan HC. 34. Slatkin NE, Rhiner M. Treatment of opiate-related seda- Effect of combining naloxone and morphine for intra- tion: utility of the cholinesterase inhibitors. J Support venous patient-control ed analgesia. Anesthesiology 35. Bruera E, Strasser F, Shen L, Palmer JL, Wil ey J, Driver 27. Cepeda MS, Alvarez H, Morales O, Carr DB. Addition LC, et al. The effect of donepezil on sedation and other of ultralow dose naloxone to postoperative morphine symptoms in patients receiving opioids for cancer pain: a PCA: unchanged analgesia and opioid requirements pilot study. J Pain Symptom Manage 2003;26:1049-54.
but decreased incidence of opioid side effects. Pain 36. Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anaesth 1995;42:891-903.
28. Hirayama T, Ishii F, Yago K, Ogata H. Evaluation of 37. Zylicz Z, Smits C, Krajnik M. Paroxetine for pruritus the effective drugs for the prevention of nausea and in advanced cancer. J Pain Symptom Manage 1998; vomiting induced by morphine used for postoperative pain: a quantitative systematic review. Yakugaku Zasshi 2001;121:179-85.
38. Brown NJ, Roberts LJ. Histamine, bradykinin, and their antagonists. In: Goodman LS, Hardman JG, Limbird LE, 29. Yee JD, Berde CB. Dextroamphetamine or methylphe- Gilman AG, eds. Goodman & Gilman’s the Pharmaco- nidate as adjuvants to opioid analgesia for adolescents logic Basis of Therapeutics. 10th ed. New York, N.Y.: with cancer. J Pain Symptom Manage 1994;9:122-5.
30. Christo PJ. Opioid effectiveness and side effects in chronic pain. Anesthesiol Clin North Am 2003;21:699-713.
1354  American Family Physician
Volume 74, Number 8October 15, 2006

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