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 copyrig[email protected] for copyright questions and/or permission requests. Opioid-Induced Adverse Effects sORT: KEY RECOMMENDATIONs FOR PRACTICE
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 8 ◆ October 15, 2006Opioid-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, 2006 ◆ Volume 74, Number 8American 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
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 8 ◆ October 15, 2006Opioid-Induced Adverse Effects
TABLE 2 selected Medications for Treating Opioid-Induced Constipation Bulk-forming
$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
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
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 8 ◆ October 15, 2006Opioid-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. REFERENCEs
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, 2006 ◆ Volume 74, Number 8American 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 8 ◆ October 15, 2006
Motorola Semiconductor National Semiconductor Philips Semiconductors international users and manufacturers group Wolfhard Lawrenz Worldwide Status of CAN - Present and Future Abstract CAN network protocol originally had been invented for automotive applications. Because of its characteristics, its robustness in conjunction with its excellent performance/price ratio CAN very soon
phase-out period numbering a few years. The new bill willoffer a simplified form as companies will be either widelyand a closely-held company - depending on the number orIf you register as a close corporation or a private companyyou will need to pay an annual return to Companies andIntellectual Property Registration Office (Cipro) to continuemaking use of your business's registered name. T