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Official reprint from UpToDate www.uptodate.com ©2016 UpToDate

AuthorsRussell K Portenoy, MDZankhana Mehta, MDEbtesam Ahmed, PharmD, MS

Section EditorJanet Abrahm, MD

Deputy EditorDiane MF Savarese, MD

Cancer pain management with opioids: Prevention and management of side effects

All topics are updated as new evidence becomes available and our peer review process is complete.Literature review current through: Feb 2016. | This topic last updated: Aug 04, 2015.

INTRODUCTION — Opioids are widely used for treatment of cancer pain because of their safety, multiple routesof administration, ease of titration, reliability, and effectiveness for all types of pain (ie, somatic, visceral,neuropathic). (See "Assessment of cancer pain", section on 'Inferred pathophysiology (types of cancer pain)'.)

Opioids can produce dose­limiting side effects, the most common of which are constipation and mental clouding.There is marked interindividual variability in the sensitivity to adverse effects from opioids, which may be due togenetic differences, age, comorbidity, or interactions with other drugs.

Side effect management is a key element of opioid therapy for cancer pain. Effective treatment of side effectsincreases the likelihood of a favorable outcome. Side effects are a major contributor to the phenomenon ofundertreatment of cancer pain. (See "Cancer pain management: General principles and risk management forpatients receiving opioids", section on 'The problem of undertreatment'.)

In general, there are three approaches to treating adverse effects from opioids: symptomatic management, dosereduction, and changing to a different opioid or route of administration. Although symptomatic managementstrategies are based upon anecdotal experience or represent an extrapolation of approaches directed againstsimilar symptoms that are caused by other mechanisms, they are widely accepted. (See "Cancer painmanagement with opioids: Optimizing analgesia", section on 'Practical considerations in opioid use'.)

This topic review will cover the prevention and management of specific adverse events in patients receiving opioidtherapy for cancer pain. Assessment of cancer pain, an overview of specific cancer pain syndromes, the clinicaluse of opioid analgesics and non­opioid analgesics (including adjuvant analgesics), and non­pharmacologicmethods of cancer pain management are covered elsewhere. (See appropriate topic reviews).

BOWEL ISSUES — It has long been recognized that opioids affect gastrointestinal motility. These effects usuallyare manifest as constipation, but bloating, early satiety, and pain are possible. Occasionally, patients develop ileusor a syndrome characterized by a relatively high level of abdominal pain. When pain is significant, the term"narcotic bowel syndrome" has sometimes been applied [1]. The etiology of pain is unknown. The phenomenon ofvisceral hyperalgesia is known to occur in functional GI disorders, and it may be that some patients whoexperience pain do so because the increased non­propulsive motility associated with opioids interacts with thisunderlying pathophysiology. Although theoretically this syndrome could be related to opioid­induced hyperalgesia,there is no evidence linking them to the same processes. (See 'Opioid­induced hyperalgesia' below.)

Constipation is the most common and persistent side effect from opioid analgesics [2]. Among opioid­treatedcancer patients, constipation occurs in approximately 10 to 15 percent, and it significantly impacts quality of life aswell as opioid use patterns, resource utilization, and costs [3,4].

Contributory factors — Multiple factors contribute to the development of constipation in patients receiving opioidsfor cancer pain:

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Opioids bind to specific receptors in the gastrointestinal tract and central nervous system to reduce bowelmotility by both direct and anticholinergic mechanisms.

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Not all opioid formulations are equally constipating. Although the results of randomized trials are conflicting [5­8],two systematic reviews concluded that there is less constipation with transdermal fentanyl than with oralsustained release morphine to [9,10]. (See "Cancer pain management with opioids: Optimizing analgesia", sectionon 'Fentanyl'.)

Prevention and management — All patients with predisposing factors (eg, advanced age, immobility, poor diet,intraabdominal pathology, neuropathy, hypercalcemia, concurrent use of other constipating drugs) should beconsidered for prophylactic laxative therapy when opioid treatment is initiated. Conventionally, this isaccomplished with a contact cathartic (eg, senna 2 tablets at bedtime) with or without [11] a stool softener (eg,docusate 100 mg orally twice daily) or daily administration of an osmotic laxative (eg, lactulose 30 ml daily orpolyethylene glycol two tablespoons daily). In patients who are lactose­intolerant, lactulose may cause excessivegas and abdominal pain, cramping, and bloating; it should be avoided in these patients [12].

If constipation develops or worsens in parallel with changes in the opioid regimen, no further evaluation is needed.However, when there is no clear precipitant, an assessment for alternative or contributory causes should beundertaken. This assessment includes history, physical examination (including a rectal examination), and, asnecessary, laboratory evaluation, imaging studies, or colonoscopy. Potentially remediable contributors toconstipation should be managed appropriately.

Some patients are able to improve bowel function by dietary modifications, including increased consumption offluids and dietary fiber. Fiber should be discontinued, however, if the patient is debilitated, bowel obstruction issuspected, or hydration has been difficult to maintain. These factors may predispose to the worsening ofobstructive symptoms when fiber is introduced into the diet. If possible, physical activity also should be increased.When care must be provided to the patient, privacy and convenience during defecation should be ensured.

Patients who have passed no stool in several days and who have no evidence of bowel obstruction or ileus arelikely to be impacted. It is often possible to clear the rectal vault and lower sigmoid colon with a mineral oil enemafollowed by an irritant enema, but manual disimpaction may be required. Once an impaction has been ruled out orcleared, laxative therapy may be started.

There are numerous options for laxative therapy (table 1) and no data to suggest that any one approach is superiorto any other. In a Cochrane systematic review of management of constipation in palliative care patients, fourrandomized trials comparing different kinds of laxatives showed no significant differences among them [13]. Thespecific approach selected should be consistent with patient preference (table 2). If one approach is ineffective, analternative should be tried.

A simple oral regimen using an osmotic agent or a contact cathartic is a reasonable starting point, but many otherstrategies exist. Before proceeding to an approach typically considered for refractory cases, the conventionalstarting strategies can be switched (from a contact cathartic to an osmotic cathartic, or vice versa) and doseescalation can be considered (table 2).

Management of refractory cases — There are many approaches to consider when patients do not respond toconventional first­line therapies. Some of these treatments, such as the use of an acetylcholinesterase inhibitor(eg, donepezil), the prostaglandin analog misoprostol, or colchicine, are supported by very limited data. Others,including the opioid antagonists and lubiprostone, are supported by high­quality evidence [14] and are FDA­approved for this indication.

Longer gastrointestinal transit time causes excessive water and electrolyte reabsorption from feces, anddecreased biliary and pancreatic secretion further dehydrates stool.

Concurrent use of other constipating drugs (eg, tricyclic antidepressants), dehydration, advancing age,immobility, metabolic abnormalities (eg, hypercalcemia), chemotherapy (particularly treatment with the vincaalkaloids) and tumor­related bowel obstruction may also contribute. (See "Enterotoxicity of chemotherapeuticagents", section on 'Constipation'.)

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Opioid antagonists — Opioid antagonists are useful to treat refractory constipation due to opioid agonists, butthese agents should be avoided in the presence of bowel obstruction.

Methylnaltrexone — The best studied opioid antagonist at present is methylnaltrexone, a peripherallyacting opioid antagonist that is specifically approved for opioid­induced constipation. It has a restricted ability tocross the blood brain barrier and does not induce symptoms of opioid withdrawal. It is available in an injectableformulation only.

The efficacy of methylnaltrexone for the treatment of opioid­induced constipation has been shown in threerandomized trials and confirmed in two separate meta­analyses [13,14]. In the latest analysis of six placebo­controlled trials totaling 1610 patients (mainly with chronic noncancer pain [15­20]), the relative risk of continuedconstipation was significantly lower with methylnaltrexone (RR 0.66, 95% CI 0.54­0.84) [14].

Methylnaltrexone is given subcutaneously once every other day, and the frequency of administration can beincreased if needed but should not exceed once daily. The approved dosage is 8 mg for patients weighing 38 to 61kg, and 12 mg for those weighing 62 to 114 kg; for those outside these ranges, the recommended dose is 0.15mg/kg. Long­term administration of methylnaltrexone is feasible [21].

Higher doses may provide additional benefit, although the data are limited. In the trial described above, a subgroupof 41 patients received dose escalation during the second week of therapy because of limited effectiveness (20 inthe methylnaltrexone group, 21 in the placebo group at an equivalent volume) [15]. The fraction of patients whohad a bowel movement within four hours of increasing the methylnaltrexone dose to 0.3 mg/kg was 24 percent(compared to 15 percent within four hours of the prior dose of 0.15 mg/kg). The corresponding rates in the placebogroup were 8 percent before, and 7 percent after dose escalation. The pattern of adverse events in patients whohad dose escalation did not differ in either group.

Concerns have been raised about severe abdominal pain and bowel perforation in patients with advanced cancerwho were receiving methylnaltrexone for opioid­induced constipation [22­24]. These concerns led the FDA to issuea warning for physicians to use caution in administering methylnaltrexone to patients with known or suspectedlesions in the intestinal wall, and to stop the drug immediately for worsening of gastrointestinal symptoms.

Oral agents — Orally­administered opioid antagonists also are available for treatment of refractoryconstipation. Oral naloxone (1 to 12 mg), an opioid antagonist, has been used to treat opioid­induced constipation;in a meta­analysis of four placebo­controlled randomized trials (798 patients, predominantly receiving opioids fornon­cancer­related pain [25­28]), the relative risk for continued constipation was significantly lower with naloxone(RR 0.64, 95% CI 0.56­0.78) [14]. However, it is 3 percent bioavailable with oral administration, and for thisreason, may reverse systemic opioid effects, potentially worsening pain or inducing withdrawal effects.

A fixed ratio combination of oxycodone plus naloxone is available commercially (Targin and Targinact) in Germany,Canada, and some other countries. Experience with this agent suggests that naloxone can be given safely topatients with chronic cancer and non­cancer pain, yielding less constipation and no compromise in analgesicefficacy (in the approved dosage range) or safety compared to oxycodone alone. In Canada and some othercountries the fixed combination is approved for treatment of chronic pain and relief or prevention of opioid­inducedconstipation in patients who require an opioid. Due to the naloxone component, pre­ and post operative use is notrecommended.

A long­acting formulation of oxycodone plus naloxone (Targiniq ER) is approved in the US for treatment ofmoderate to severe pain for which alternative treatment options are inadequate [25,29]. However, there is nolabeled indication for relief or prevention of opioid­induced constipation.

A new naloxone sustained­release capsule appears to be safe and efficacious for the treatment of opioid­inducedconstipation without compromising the desired opioid analgesic effects [30]. However, this formulation is notavailable or approved in any country as of yet.

Naloxegol, a pegylated form of naloxone, appears to be effective against refractory opioid­induced constipation in

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patients with non­cancer­related pain, without reversal of the analgesic effect [31]. In the United States, naloxegolis approved for treatment of opioid­induced constipation in patients with non­cancer pain. (See "Overview of thetreatment of chronic pain", section on 'Constipation'.)

Alvimopan is an orally administered peripherally acting mu receptor antagonist that is approved in the US for short­term inpatient management of postoperative ileus in patients undergoing bowel resection. (See "Postoperativeileus" and "Measures to prevent prolonged postoperative ileus", section on 'Peripheral acting mu­opioid receptorantagonists'.)

The benefit of alvimopan for opioid­induced constipation was shown in a meta­analysis of four randomized trials(1693 patients, all with non­cancer related pain [32­35]), in which the relative risk for continued constipation withalvimopan was 0.71 (95% CI 0.65­0.78) [14]. In one of the trials, active treatment did not increase the requirementfor opioid medication or increase pain intensity scores [34]. The drug was specifically not approved for opioid­induced constipation because an earlier unpublished 12­month safety study in patients treated with opioids forchronic pain had shown more reports of myocardial infarction in patients treated with alvimopan than with placebo[36]. Although a causal relationship has not been established, without more information, the use of this drug in theambulatory setting for opioid­induced constipation in cancer patients cannot be recommended.

Lubiprostone — Lubiprostone is a type­2 chloride channel activator, which induces secretion of fluid in theintestine. Efficacy in opioid­induced constipation has been confirmed in at least two randomized controlled trials[37,38]. In the larger of these trials, 418 patients with chronic non­cancer pain and opioid­induced constipationwere randomly assigned to lubiprostone (24 micrograms twice daily) or placebo for 12 weeks [37]. Patientsreceiving lubiprostone had significant improvement in spontaneous bowel movements, abdominal discomfort,straining, constipation severity, and stool consistency. Patients rated lubiprostone effectiveness to be higher thanplacebo during 11 of the 12 weeks, and side effects were largely tolerable (nausea: lubiprostone 17 versus 6percent with placebo; diarrhea 10 versus 3 percent; and abdominal distention 8 versus 2 percent).

Like naloxegol, lubiprostone is approved for the treatment of opioid­induced constipation in patients receiving opioidtherapy for chronic non­cancer pain.

SOMNOLENCE AND MENTAL CLOUDING — Opioid therapy can cause somnolence or mental clouding.Symptoms typically wane over a period of days or weeks, but are persistent in some patients, particularly in thosewith other contributing factors (eg, early dementia or the use of other centrally acting drugs).

The characteristics of drug­induced somnolence and mental clouding can vary widely. The degree of cognitiveimpairment ranges from slight inattention or fatigue, to befuddlement to disorientation, severe memory impairment,or extreme confusion and delirium. Perceptual disorders, which themselves range from increased dreaming andhypnagogic illusions to frank hallucinations, can occur, as can mood disturbances. In this population, mooddisturbance is more often negative (irritability, depressed mood, dysphoria) than positive (contentment, euphoria).

The incidence of cognitive dysfunction in patients receiving opioid therapy for cancer pain is not wellcharacterized. A prospective, multicenter cross­sectional study of 1915 adult patients with cancer who receivedopioids for at least three days suggested that possible or definite cognitive dysfunction (as assessed by MiniMental Status Examination (MMSE)) scores lower than 27 was present in one­third of treated patients [39]. Riskfactors for cognitive dysfunction included a diagnosis of lung cancer, daily opioid doses (oral morphine equivalents)of ≥400 mg, older age, low performance status, and time since cancer diagnosis <15 months; the presence ofbreakthrough pain was associated with better cognitive function. (See "Evaluation of cognitive impairment anddementia", section on 'Mini­Mental State Examination'.)

Like other symptoms associated with opioid therapy, the decision to pursue additional evaluation is a clinicaljudgment that is influenced by the likelihood that other factors may be contributing. If the relationship of thesymptoms to the drug or other factors is clear, further evaluation may not be needed.

Management — A stepwise approach to management includes the following:

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Psychostimulants — There is a limited clinical literature, mainly anecdotal experience, supporting the use ofcentral nervous system stimulants to offset opioid­induced sedation [40,41]. The largest experience is withmethylphenidate and modafinil, two agents used commonly for cancer­related fatigue. (See "Cancer­relatedfatigue: Treatment".)

The therapeutic effects of psychostimulants sometimes wane over time. Whether this reflects tolerance orsymptom progression is unknown, but the phenomenon should be recognized. Dose escalation of thepsychostimulant or a switch to an alternative drug may be useful.

All psychostimulants can produce side effects such as tremulousness, insomnia, anorexia, and anxiety,tachycardia, and hypertension. Given the potential for these adverse effects, relative contraindications to the use

Obvious contributing causes (eg, primary central nervous system pathology, metabolic disturbances,dehydration, other drugs) should be addressed and treated, if this is feasible and consistent with the goals ofcare. Nonessential centrally­acting medications should be reduced or eliminated.

The opioid regimen should then be evaluated. If analgesia is satisfactory, it may be possible to reduce thedose, but this is often limited by recrudescence of pain. The impact of an empiric 25 percent dose reductionon both pain control and side effects is usually clear within a short time frame.

On the other hand, if analgesia is unsatisfactory, opioid rotation may be tried, or an adjuvant (coanalgesic)may be initiated in an attempt to achieve an opioid­sparing effect. (See "Cancer pain management withopioids: Optimizing analgesia", section on 'Opioid poorly responsive pain' and "Cancer pain management:Adjuvant analgesics (coanalgesics)" and "Cancer pain management: Use of acetaminophen and nonsteroidalantiinflammatory drugs".)

Drug treatment directed at the symptom may be considered.

Methylphenidate – Benefit for methylphenidate in patients receiving opioids has been suggested in two ofthree small randomized trials [42­44]. A systematic review concluded that this represented weak evidence insupport of the use of methylphenidate given that the quality of the negative study was lower than that of thetwo positive studies [45]. Furthermore, treatment with methylphenidate was associated with anxiety,hallucinations, and sweating.

Methylphenidate is typically initiated at a starting dose of 5 mg in the morning and at noon, or a comparabledose of one of the long­acting, modified­release formulations. The dose usually requires titration until benefitsoccur or side effects supervene. Most patients experience benefit at doses well below 60 mg/day, but somerequire considerably higher doses.

Modafinil – Modafinil, a nonamphetamine psychostimulant, appears to cause fewer sympathomimetic sideeffects than methylphenidate and other psychostimulants. Evidence to support benefit of modafinil to preventopioid­induced sedation is limited to retrospective reports of patients with pain of nonmalignant origin [46­48].

Modafanil is initiated at 100 to 200 mg per day and may require dose escalation to optimize effects. Mostpatients require no more than 600 mg per day and only occasional patients require twice daily as comparedto once daily dosing.

Other psychostimulants – Other psychostimulants that may be beneficial in the setting of opioid­inducedsedation include dextroamphetamine [49], dexmethylphenidate, atomoxetine, donepezil, and caffeine [50]. Asystematic review of treatment for opioid­related CNS symptoms concluded that the quality of the studiesinvolving dexamphetamine, caffeine and donepezil was not sufficient to make any recommendations abouttheir use [45]. These drugs are usually considered only if methylphenidate or modafinil are poorly tolerated orcontraindicated. There is very limited clinical experience with the use of the acetylcholinesterase inhibitors,such as donepezil, in the management of this side effect [51,52].

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of psychostimulants include preexisting anorexia, severe insomnia, a psychiatric disorder characterized by anxietyor paranoid ideation, significant cardiac disease, or poorly controlled hypertension. Older patients and those withearly dementing illnesses are especially susceptible to untoward psychotomimetic and cognitive disturbance.

LESS COMMON SIDE EFFECTS — Numerous other side effects are less common but widely recognized opioid­related problems.

Nausea and vomiting — Nausea frequently complicates the initiation of opioid therapy, but tolerance occursquickly and persistent nausea is infrequent. Gradual rather than rapid upward titration of the opioid dose mayprevent persistent nausea. When persistent nausea occurs, it is often in the context of other, less well­characterized gastrointestinal symptoms, including dry mouth, reflux, anorexia, early satiety, and abdominalbloating [53].

Opioids have three potentially emetogenic mechanisms: a direct effect on the chemoreceptor trigger zone,enhanced vestibular sensitivity, and delayed gastric emptying. Refractory constipation and stool impaction may becontributory. When present, they should be managed first.

Chronic nausea usually responds to the same group of drug therapies that are used for acute nausea (table 3)[54,55]. The available evidence supports use of a dopamine antagonist, such as prochlorperazine ormetoclopramide (also a prokinetic drug [56,57]), or a serotonin receptor antagonist, such as ondansetron[56,58,59], as usual first line agents (see "Characteristics of antiemetic drugs"). Chronic use of the serotoninreceptor antagonists, however, causes constipation, which in itself can be a cause of nausea.

A small observational retrospective study found that risperidone 1 mg daily orally [60] decreased refractory nauseaand vomiting thought to be due to opioids in patients with advanced cancer. Furthermore, in the setting ofchemotherapy­induced nausea and vomiting, olanzapine has been shown to reduce chronic nausea. It seemsreasonable to try an atypical antipsychotic such as olanzapine or risperidone in refractory cases. (See "Preventionand treatment of chemotherapy­induced nausea and vomiting", section on 'Olanzapine'.)

The specific clinical scenario may also suggest benefit from other strategies:

Opioid rotation or a change in route of administration could also be considered. In two small studies, a switch fromthe oral to the subcutaneous route produced significantly less nausea and vomiting [62,63]. In contrast, there areconflicting data as to the benefit of switching from the oral to the rectal route [62,64­66]. (See "Cancer painmanagement with opioids: Optimizing analgesia", section on 'Selecting the route of administration' and "Cancerpain management with opioids: Optimizing analgesia", section on 'Opioid poorly responsive pain'.)

Myoclonus — Myoclonus (uncontrollable spasms of certain muscle groups) is a common dose­related effect ofopioids that is often associated with somnolence and mental clouding. The etiology may be multifactorial, withcontributions from other drugs and/or metabolic disturbances.

The available evidence for treatment of myoclonus comes almost exclusively from published case reports. Asystematic review concluded that the available data were insufficient to confirm or refute the benefits of any drugfor the management of myoclonus [45].

If treatment is considered, the usual approach is to try a low­dose of the benzodiazepine clonazepam (0.5 mgorally every six to eight hours [67]) or lorazepam (0.5 to 1 mg orally, sublingually, or IV q 1 to 2 hours). A trial of an

Some patients who experience nausea with movement or nausea associated with vertigo may respond to ananticholinergic drug such as scopolamine or an antihistamine such as meclizine [61].

If nausea follows meals or is accompanied by postprandial vomiting, metoclopramide is an appropriatechoice.

Patients with epigastric pain or burning should be offered a trial of a proton pump inhibitor, such aspantoprazole, or an H2 antagonist, such as ranitidine.

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anticonvulsant is rarely considered. A change to another opioid or the addition of an adjuvant analgesic may permita reduction in opioid dose, relieving the myoclonus. (See "Cancer pain management with opioids: Optimizinganalgesia", section on 'Opioid poorly responsive pain' and "Cancer pain management: Adjuvant analgesics(coanalgesics)".)

Opioid­induced hyperalgesia — Opioid­induced hyperalgesia (OIH) is a state of nociceptive sensitization that iscaused by exposure to opioids. This state is characterized by a paradoxical response whereby a patient receivingopioids for the treatment of pain may actually become more sensitive to certain painful stimuli and in some cases,experience pain from ordinarily non­painful stimuli (allodynia) [68]. The increased pain sensitivity is diffuse andoften manifests beyond the area of original pain, it is independent of the condition for which the opioids wereinitially prescribed, and persists, or even worsens after dose escalation of opioids [69­71].

Although solid evidence for the existence of OIH in patients with chronic or cancer­related pain is lacking [72], thephenomenon of OIH, linked to the development of analgesic tolerance [73,74], has been clearly demonstrated inanimal models, and has relevance in the clinical setting [68,75,76].

Nevertheless, individual patients who demonstrate a loss of opioid effect in the absence of progressive illness (ie,develop analgesic tolerance), or develop a syndrome of worsening or more diffuse pain, with tremulousness andpossibly confusion, during a period of aggressive opioid escalation, may be demonstrating OIH. Clinicians shouldbe aware of this phenomenon, which often occurs when moaning that arises from delirium at the end of life ismistaken for pain, and extra boluses of opioids are given. All patients with worsening or more diffuse pain during aperiod of aggressive opioid escalation should be evaluated for delirium and OIH.

There is no well­established treatment for OIH [69]. When suspected, it is reasonable to consider opioid rotation[77], or the use of a non­opioid strategy for pain control.

Effects on the hypothalamic­pituitary­adrenal axis — Opioids affect the functioning of the hypothalamic­pituitary­adrenal axis, resulting in increased levels of prolactin, decreased levels of sex hormones or both [78­80].The potential for clinically significant effects related to the hypogonadism (ie, sexual dysfunction, infertility, fatigue,accelerated bone loss and mood disturbance) is only now receiving attention [78]. (See "Clinical manifestations ofhypopituitarism".)

The relevance of these issues to patients treated for advanced malignancy is unclear. However, in the setting ofless advanced disease, these problems may be relevant to broader efforts to address quality of life concerns. Ifthe goals of care support evaluation, opioid­treated patients with cancer pain who complain of fatigue, depressedmood, or sexual dysfunction should have levels of sex hormones measured. If they are low, and the clinicalsetting is appropriate, repletion therapy (testosterone in men, estrogen in women) should be considered.

Respiratory depression — Respiratory depression is commonly considered a serious adverse effect of the opioiddrugs, but it is rarely a problem when therapy is administered according to accepted guidelines [81­84]. Toleranceusually develops rapidly to this effect, allowing escalation of the dose by typical increments without clinicallysignificant respiratory effects. (See "Cancer pain management with opioids: Optimizing analgesia", section on'Dose titration'.)

Patients may be at risk of clinically significant respiratory depression when opioids are titrated rapidly, when theyare administered in the setting of a sleep apnea syndrome or some other serious cardiopulmonary comorbidity thatlimits ventilatory reserve, or when the opioid is combined with a sedative­hypnotic. Even in the latter setting,however, cautious selection of the initial dose and conservative incremental dose titration limit the risk ofrespiratory depression.

Nonetheless, clinicians should recognize that a syndrome of opioid­induced sleep­disordered breathing isbecoming recognized as a risk during long­term opioid therapy. Patients who are predisposed to sleep apnea byvirtue of obesity, short neck, or a history of snoring should have opioids administered with particular caution. Othercentrally acting drugs, particularly the benzodiazepines, should be added only at low doses and with careful

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monitoring. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults" and "Sleep relatedbreathing disorders in adults: Definitions".)

Among patients receiving opioids for cancer pain, it is common for staff to attribute any respiratory problem to theopioid. However, opioids produce somnolence and slowed respirations; respiratory distress that is associated withtachypnea and anxiety is never a primary opioid event.

It is also essential to recognize that partial reversal of respiratory disturbances by naloxone in the opioid­treatedpatient does not mean that the opioid is the primary cause of the problem, particularly if respiratory problemsdeveloped during a period of relatively stable dosing. Regardless of a naloxone response, a search for a concurrentacute process (eg, pulmonary embolism, cerebral edema), which may have combined with subclinical opioideffects, is often appropriate in the cancer population.

Management — Naloxone should not be given to somnolent but easily arousable patients, whether or not theyhave a respiratory rate less than 10 when sleeping. If hypoventilation and moderate sedation occur near theexpected peak of opioid activity, it is best to withhold further opioids until the respiratory rate rises or pain returns.Naloxone should be reserved for symptomatic respiratory depression or for progressive obtundation suggestive ofimminent respiratory failure. The risks of abstinence, aspiration and severe pain associated with the use ofnaloxone relatively contraindicate its use in other situations.

If needed, it is best to administer naloxone using small bolus injections of dilute solution (ie, by diluting 0.4 mg [1mL] ampule with 9 mL of normal saline for a total volume of 10 mL) which should be titrated against respiratoryrate. Repeated doses are often necessary as naloxone's half­life is shorter than that of most opioids. Patientsreceiving sustained­release opioid formulations or long half­life drugs (eg, methadone or levorphanol) may require analoxone infusion to prevent recurrence of respiratory depression.

Pruritus — Pruritus is observed in 2 to 10 percent of patients receiving chronic opioids [85]. The exactmechanism underlying pruritus is uncertain [86]. In most cases, pruritus does not appear to represent an allergicreaction. Although morphine is reported to cause histamine release from mast cells, other opioids (ie, fentanyl,sufentanil, and oxymorphone) are less likely to produce histamine release, yet they are still associated withpruritus [55,87,88]. There is increasing evidence that opioid­induced pruritus is mediated through central mu opioidreceptors [89].

There are no prospective studies on the treatment of opioid­induced pruritus. Despite the controversy as to the roleof histamine in opioid­induced pruritus, antihistamines are commonly used as first­line agents, with varyingdegrees of success [55,86]. Anecdotal experience suggests benefit from paroxetine [90]. Another option is opioidrotation [91].

Low doses of opioid antagonists (eg, nalmefene 10 to 25 micrograms IV, nalbuphine 1 to 5 mg IV/IM) are effectivefor treatment of pruritus in patients with non­cancer pain receiving short­term opioids in the postoperative setting,without reversal of opioid analgesia [86,92,93]. However, long­term use of opioid antagonists in patients withcancer pain who are experiencing prolonged opioid­induced pruritus has not been investigated [92].

Allergic reaction — True opioid allergy is very rare, but both contact dermatitis and systemic hypersensitivityhave been reported. Based upon theoretical considerations, it is commonly taught that a patient who continues toneed an opioid after demonstrating an allergy to morphine or a semisynthetic opioid (eg, hydromorphone oroxycodone) should be considered for a trial of one of the synthetic opioids (eg, fentanyl or methadone), along withcoadministration of a histamine antagonist and a glucocorticoid. However, there is no evidence that cross­sensitivity is reduced by this maneuver as compared to a switch to another alkaloid or semisynthetic opioid.

Urinary retention — Opioids can cause urinary retention. A peripheral effect on nerves that innervate the bladderincreasing the tone of the urinary bladder sphincter is possible, and direct binding to spinal opioid receptorscausing total bladder relaxation may contribute [94­96].

Preventive strategies have not been established. Although concomitant use of NSAIDs diminishes some opioid

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side effects (presumably by their opioid sparing effect), there is no impact on urinary retention [97,98].

Initial management of acute urinary retention consists of prompt relief through catheterization of the bladder. Aneffort should be made to reduce the dose of drugs that may be contributing to urinary retention, such as drugs withanticholinergic effects.

Naloxone is effective in reversing urinary retention, but also reverses the analgesic effect in the postoperativesetting [99]. There is a single case report of successful use of nalbuphine in the postoperative setting; it waseffective at reversing the urinary retention with sustained analgesic effect [100]. Anecdotally, some patientsappear to respond to drugs used to treat urinary retention related to prostatic hypertrophy, such as the alpha­1blockers doxazosin or tamsulosin. (See "Medical treatment of benign prostatic hyperplasia", section on 'Alpha­1­adrenergic antagonists'.)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and"Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5 to 6 gradereading level, and they answer the four or five key questions a patient might have about a given condition. Thesearticles are best for patients who want a general overview and who prefer short, easy­to­read materials. Beyondthe Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are writtenat the 10 to 12 grade reading level and are best for patients who want in­depth information and are comfortablewith some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e­mail thesetopics to your patients. (You can also locate patient education articles on a variety of subjects by searching on"patient info" and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS — Opioid therapy is the first­line approach for moderate or severechronic cancer pain. Opioids can produce dose­limiting side effects, the most common of which are constipationand mental clouding. Effective treatment of side effects increases the likelihood of a favorable outcome, and sideeffect management is a key element of opioid therapy for cancer pain.

In general, there are three approaches to treating adverse effects from opioids: symptomatic management, dosereduction, or changing to a different opioid or route of administration. (See "Cancer pain management with opioids:Optimizing analgesia", section on 'Practical considerations in opioid use'.)

Prevention and management of constipation — The most common and persistent side effect from opioidanalgesics is constipation. (See 'Bowel issues' above.)

For all patients with predisposing factors, including advanced age, immobility, poor diet, intraabdominal pathology,neuropathy, hypercalcemia, or use of other constipating drugs, we suggest prophylactic laxative therapy whenopioid treatment is initiated (Grade 2C).

Opioid­induced constipation should be managed aggressively. For patients who develop worsening constipationduring stable opioid dosing despite the use of a bowel regimen, a diagnostic evaluation (including a rectalexamination) should be pursued if there is no alternative explanation. There are numerous options supplementingthe conventional first­line approaches to opioid­induced constipation (table 1) and no data to suggest that any oneapproach is superior to any other. The specific approach selected should be consistent with patient preference(table 2) and usually begins with the coadministration of docusate (100 mg orally twice daily) and senna (twotablets at bedtime initially, then dose escalating if needed) or daily administration of polyethylene glycol. Acommon alternative approach is another osmotic agent (eg, lactulose [except in lactose­intolerant patients]).

Some cancer patients also are able to improve bowel function by dietary modifications (increased consumption offluids and soluble dietary fiber) and increased physical activity. Fiber should not be increased if the patient isdebilitated, bowel obstruction is suspected, or hydration has been difficult to maintain. (See 'Prevention and

th th

th th

Basics topic (see "Patient information: Managing pain when you have cancer (The Basics)")

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management' above.)

For refractory cases, there are numerous approaches (table 1) including opioid antagonist therapy and lubiprostone,which are specifically approved for this indication. For most patients we suggest methylnaltrexone (Grade 2A).However, clinicians should use caution in administering methylnaltrexone to patients with known or suspectedlesions in the intestinal wall, and should stop the drug immediately for worsening of gastrointestinal symptoms.(See 'Management of refractory cases' above.)

Sedation and cognitive impairment — Opioid therapy can cause somnolence or mental clouding, which typicallywanes over a period of days or weeks, but is persistent in some patients. The severity is widely variable.

A stepwise approach to treatment includes the following:

Other side effects — Management of other opioid­induced side effects is empiric.

ACKNOWLEDGMENT — We are saddened by the death of J Andrew Billings, MD, who passed away inSeptember 2015. UpToDate wishes to acknowledge Dr. Billings' many contributions to palliative care, in particular,his work as our Editor­in­Chief and Section Editor for Non Pain Symptoms: Assessment and Management.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Grunkemeier DM, Cassara JE, Dalton CB, Drossman DA. The narcotic bowel syndrome: clinical features,

Obvious contributing causes should be treated, if feasible and consistent with the goals of care.

If analgesia is satisfactory, an empiric trial of opioid dose reduction is a reasonable first step. If analgesia isunsatisfactory, opioid rotation may be beneficial, or coanalgesics may be initiated or increased in order toachieve an opioid­sparing effect.

As an alternative strategy, we suggest an empiric trial of a psychostimulant (Grade 2B). Options includemethylphenidate or modafinil. (See 'Psychostimulants' above.)

Nausea frequently complicates the initiation of opioid therapy, but tolerance occurs quickly; persistentnausea is infrequent. Chronic nausea usually responds to the same group of drug therapies that are used foracute nausea (table 3). Other options include a change to the subcutaneous route of administration, or opioidrotation. (See 'Nausea and vomiting' above.)

Myoclonus is a spasm of certain muscle groups that is typically associated with high­doses of opioids.Therapeutic options include clonazepam 0.5 mg orally every six to eight hours or lorazepam 0.5 to 1 mgorally, sublingually or intravenously every two to three hours, an anticonvulsant, or opioid rotation. (See'Myoclonus' above.)

The phenomenon of opioid­induced hyperalgesia should be considered in the individual patient whodemonstrates worsening pain with tremulousness, and possibly generalized allodynia and confusion, as theopioid dose is aggressively escalated, especially if there is no evidence of rapidly progressive illness or newpathology. Therapeutic options include opioid rotation or a switch to a non­opioid analgesic. (See 'Opioid­induced hyperalgesia' above.)

Respiratory depression is commonly considered a serious adverse effect of the opioid drugs, but it is rarely aproblem when therapy is administered according to accepted guidelines. (See 'Respiratory depression'above.)

Opioid­induced pruritus affects up to 10 percent of patients treated with opioids. Options for managementinclude antihistamines, paroxetine, or opioid rotation. (See 'Pruritus' above.)

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pathophysiology, and management. Clin Gastroenterol Hepatol 2007; 5:1126.2. Clemens KE, Klaschik E. Management of constipation in palliative care patients. Curr Opin Support PalliatCare 2008; 2:22.

3. Candrilli SD, Davis KL, Iyer S. Impact of constipation on opioid use patterns, health care resourceutilization, and costs in cancer patients on opioid therapy. J Pain Palliat Care Pharmacother 2009; 23:231.

4. Bell T, Annunziata K, Leslie JB. Opioid­induced constipation negatively impacts pain management,productivity, and health­related quality of life: findings from the National Health and Wellness Survey. JOpioid Manag 2009; 5:137.

5. Wirz S, Wittmann M, Schenk M, et al. Gastrointestinal symptoms under opioid therapy: a prospectivecomparison of oral sustained­release hydromorphone, transdermal fentanyl, and transdermal buprenorphine.Eur J Pain 2009; 13:737.

6. Ahmedzai S, Brooks D. Transdermal fentanyl versus sustained­release oral morphine in cancer pain:preference, efficacy, and quality of life. The TTS­Fentanyl Comparative Trial Group. J Pain SymptomManage 1997; 13:254.

7. van Seventer R, Smit JM, Schipper RM, et al. Comparison of TTS­fentanyl with sustained­release oralmorphine in the treatment of patients not using opioids for mild­to­moderate pain. Curr Med Res Opin 2003;19:457.

8. Wong JO, Chiu GL, Tsao CJ, Chang CL. Comparison of oral controlled­release morphine with transdermalfentanyl in terminal cancer pain. Acta Anaesthesiol Sin 1997; 35:25.

9. Tassinari D, Sartori S, Tamburini E, et al. Transdermal fentanyl as a front­line approach to moderate­severepain: a meta­analysis of randomized clinical trials. J Palliat Care 2009; 25:172.

10. Tassinari D, Sartori S, Tamburini E, et al. Adverse effects of transdermal opiates treating moderate­severecancer pain in comparison to long­acting morphine: a meta­analysis and systematic review of the literature.J Palliat Med 2008; 11:492.

11. Tarumi Y, Wilson MP, Szafran O, Spooner GR. Randomized, double­blind, placebo­controlled trial of oraldocusate in the management of constipation in hospice patients. J Pain Symptom Manage 2013; 45:2.

12. Teuri U, Vapaatalo H, Korpela R. Fructooligosaccharides and lactulose cause more symptoms in lactosemaldigesters and subjects with pseudohypolactasia than in control lactose digesters. Am J Clin Nutr 1999;69:973.

13. Candy B, Jones L, Goodman ML, et al. Laxatives or methylnaltrexone for the management of constipation inpalliative care patients. Cochrane Database Syst Rev 2011; :CD003448.

14. Ford AC, Brenner DM, Schoenfeld PS. Efficacy of pharmacological therapies for the treatment of opioid­induced constipation: systematic review and meta­analysis. Am J Gastroenterol 2013; 108:1566.

15. Thomas J, Karver S, Cooney GA, et al. Methylnaltrexone for opioid­induced constipation in advancedillness. N Engl J Med 2008; 358:2332.

16. Michna E, Blonsky ER, Schulman S, et al. Subcutaneous methylnaltrexone for treatment of opioid­inducedconstipation in patients with chronic, nonmalignant pain: a randomized controlled study. J Pain 2011; 12:554.

17. Yuan CS, Foss JF, O'Connor M, et al. Methylnaltrexone for reversal of constipation due to chronicmethadone use: a randomized controlled trial. JAMA 2000; 283:367.

18. Slatkin N, Thomas J, Lipman AG, et al. Methylnaltrexone for treatment of opioid­induced constipation inadvanced illness patients. J Support Oncol 2009; 7:39.

19. Anissian L, Schwartz HW, Vincent K, et al. Subcutaneous methylnaltrexone for treatment of acute opioid­induced constipation: phase 2 study in rehabilitation after orthopedic surgery. J Hosp Med 2012; 7:67.

20. Rauck R, Peppin J, Israel R, et al.. Oral methylnaltrexone for the treatment of opioid induced constipation inpatients with noncancer pain. Gastroenterology 2012; 142 (suppl1):S160.

21. Dutka J, Lowe SS, Michaud M, Watanabe S. Long­term use of methylnaltrexone for the management ofconstipation in advanced cancer. J Support Oncol 2009; 7:177.

22. Centeno C, Carranza O, Zuriarrain Y, et al. A prospective study of methylnaltrexone for opioid­inducedconstipation in advanced illness: should we use it or not? J Pain Symptom Manage 2013; 46:e1.

23. Slatkin NE, Lynn R, Su C, et al. Characterization of abdominal pain during methylnaltrexone treatment ofopioid­induced constipation in advanced illness: a post hoc analysis of two clinical trials. J Pain SymptomManage 2011; 42:754.

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24. Watkins JL, Eckmann KR, Mace ML, et al. Utilization of methylnaltrexone (relistor) for opioid­inducedconstipation in an oncology hospital. P T 2011; 36:33.

25. Simpson K, Leyendecker P, Hopp M, et al. Fixed­ratio combination oxycodone/naloxone compared withoxycodone alone for the relief of opioid­induced constipation in moderate­to­severe noncancer pain. Curr MedRes Opin 2008; 24:3503.

26. Löwenstein O, Leyendecker P, Hopp M, et al. Combined prolonged­release oxycodone and naloxoneimproves bowel function in patients receiving opioids for moderate­to­severe non­malignant chronic pain: arandomised controlled trial. Expert Opin Pharmacother 2009; 10:531.

27. Liu M, Wittbrodt E. Low­dose oral naloxone reverses opioid­induced constipation and analgesia. J PainSymptom Manage 2002; 23:48.

28. Meissner W, Leyendecker P, Mueller­Lissner S, et al. A randomised controlled trial with prolonged­releaseoral oxycodone and naloxone to prevent and reverse opioid­induced constipation. Eur J Pain 2009; 13:56.

29. Ahmedzai SH, Nauck F, Bar­Sela G, et al. A randomized, double­blind, active­controlled, double­dummy,parallel­group study to determine the safety and efficacy of oxycodone/naloxone prolonged­release tablets inpatients with moderate/severe, chronic cancer pain. Palliat Med 2012; 26:50.

30. Sanders M, Jones S, Löwenstein O, et al. New Formulation of Sustained Release Naloxone Can ReverseOpioid Induced Constipation Without Compromising the Desired Opioid Effects. Pain Med 2015; 16:1540.

31. Chey WD, Webster L, Sostek M, et al. Naloxegol for opioid­induced constipation in patients with noncancerpain. N Engl J Med 2014; 370:2387.

32. Culpepper­Morgan JA, Inturrisi CE, Portenoy RK, et al. Treatment of opioid­induced constipation with oralnaloxone: a pilot study. Clin Pharmacol Ther 1992; 52:90.

33. Sykes NP. An investigation of the ability of oral naloxone to correct opioid­related constipation in patientswith advanced cancer. Palliat Med 1996; 10:135.

34. Jansen JP, Lorch D, Langan J, et al. A randomized, placebo­controlled phase 3 trial (Study SB­767905/012)of alvimopan for opioid­induced bowel dysfunction in patients with non­cancer pain. J Pain 2011; 12:185.

35. Paulson DM, Kennedy DT, Donovick RA, et al. Alvimopan: an oral, peripherally acting, mu­opioid receptorantagonist for the treatment of opioid­induced bowel dysfunction­­a 21­day treatment­randomized clinicaltrial. J Pain 2005; 6:184.

36. Alvimopan prescribing information available online at http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=77a67dc6­35d3­48ff­9d18­292d4d442f70 (Accessed on October 15, 2014).

37. Cryer B, Katz S, Vallejo R, et al. A randomized study of lubiprostone for opioid­induced constipation inpatients with chronic noncancer pain. Pain Med 2014; 15:1825.

38. Jamal MM, Adams AB, Jansen JP, Webster LR. A randomized, placebo­controlled trial of lubiprostone foropioid­induced constipation in chronic noncancer pain. Am J Gastroenterol 2015; 110:725.

39. Kurita GP, Sjøgren P, Ekholm O, et al. Prevalence and predictors of cognitive dysfunction in opioid­treatedpatients with cancer: a multinational study. J Clin Oncol 2011; 29:1297.

40. Reissig JE, Rybarczyk AM. Pharmacologic treatment of opioid­induced sedation in chronic pain. AnnPharmacother 2005; 39:727.

41. Rozans M, Dreisbach A, Lertora JJ, Kahn MJ. Palliative uses of methylphenidate in patients with cancer: areview. J Clin Oncol 2002; 20:335.

42. Wilwerding MB, Loprinzi CL, Mailliard JA, et al. A randomized, crossover evaluation of methylphenidate incancer patients receiving strong narcotics. Support Care Cancer 1995; 3:135.

43. Bruera E, Miller MJ, Macmillan K, Kuehn N. Neuropsychological effects of methylphenidate in patientsreceiving a continuous infusion of narcotics for cancer pain. Pain 1992; 48:163.

44. Bruera E, Chadwick S, Brenneis C, et al. Methylphenidate associated with narcotics for the treatment ofcancer pain. Cancer Treat Rep 1987; 71:67.

45. Stone P, Minton O. European Palliative Care Research collaborative pain guidelines. Central side­effectsmanagement: what is the evidence to support best practice in the management of sedation, cognitiveimpairment and myoclonus? Palliat Med 2011; 25:431.

46. Cox JM, Pappagallo M. Modafinil: a gift to portmanteau. Am J Hosp Palliat Care 2001; 18:408.47. Webster L, Andrews M, Stoddard G. Modafinil treatment of opioid­induced sedation. Pain Med 2003; 4:135.

3/9/2016 Cancer pain management with opioids: Prevention and management of side effects

http://www.uptodate.com/contents/cancer­pain­management­with­opioids­prevention­and­management­of­side­effects?topicKey=PALC%2F2800&elapsedTi… 13/22

48. Prommer E. Modafinil: is it ready for prime time? J Opioid Manag 2006; 2:130.49. Kreeger L, Duncan A, Cowap J. Psychostimulants used for opioid­induced drowsiness. J Pain Symptom

Manage 1996; 11:1.50. Mercadante S, Serretta R, Casuccio A. Effects of caffeine as an adjuvant to morphine in advanced cancer

patients. A randomized, double­blind, placebo­controlled, crossover study. J Pain Symptom Manage 2001;21:369.

51. Slatkin NE, Rhiner M, Bolton TM. Donepezil in the treatment of opioid­induced sedation: report of six cases.J Pain Symptom Manage 2001; 21:425.

52. Bruera E, Strasser F, Shen L, et al. The effect of donepezil on sedation and other symptoms in patientsreceiving opioids for cancer pain: a pilot study. J Pain Symptom Manage 2003; 26:1049.

53. Wiffen PJ, Derry S, Moore RA. Impact of morphine, fentanyl, oxycodone or codeine on patientconsciousness, appetite and thirst when used to treat cancer pain. Cochrane Database Syst Rev 2014;5:CD011056.

54. Keeley PW. Nausea and vomiting in people with cancer and other chronic diseases. BMJ Clin Evid 2009;2009.

55. McNicol E, Horowicz­Mehler N, Fisk RA, et al. Management of opioid side effects in cancer­related andchronic noncancer pain: a systematic review. J Pain 2003; 4:231.

56. Hardy J, Daly S, McQuade B, et al. A double­blind, randomised, parallel group, multinational, multicentrestudy comparing a single dose of ondansetron 24 mg p.o. with placebo and metoclopramide 10 mg t.d.s. p.o.in the treatment of opioid­induced nausea and emesis in cancer patients. Support Care Cancer 2002; 10:231.

57. Laugsand EA, Kaasa S, Klepstad P. Management of opioid­induced nausea and vomiting in cancer patients:systematic review and evidence­based recommendations. Palliat Med 2011; 25:442.

58. Sussman G, Shurman J, Creed MR, et al. Intravenous ondansetron for the control of opioid­induced nauseaand vomiting. International S3AA3013 Study Group. Clin Ther 1999; 21:1216.

59. Chung F, Lane R, Spraggs C, et al. Ondansetron is more effective than metoclopramide for the treatment ofopioid­induced emesis in post­surgical adult patients. Ondansetron OIE Post­Surgical Study Group. Eur JAnaesthesiol 1999; 16:669.

60. Okamoto Y, Tsuneto S, Matsuda Y, et al. A retrospective chart review of the antiemetic effectiveness ofrisperidone in refractory opioid­induced nausea and vomiting in advanced cancer patients. J Pain SymptomManage 2007; 34:217.

61. Ferris FD, Kerr IG, Sone M, Marcuzzi M. Transdermal scopolamine use in the control of narcotic­inducednausea. J Pain Symptom Manage 1991; 6:389.

62. Cherny N, Ripamonti C, Pereira J, et al. Strategies to manage the adverse effects of oral morphine: anevidence­based report. J Clin Oncol 2001; 19:2542.

63. McDonald PP, Graham M, Clayton A, et al. Regular subcutaneous bolus morphine via an indwelling cannulafor pain from advanced cancer. Palliat Med 1991; 5:323.

64. De Conno F, Ripamonti C, Saita L, et al. Role of rectal route in treating cancer pain: a randomizedcrossover clinical trial of oral versus rectal morphine administration in opioid­naive cancer patients with pain.J Clin Oncol 1995; 13:1004.

65. Babul N, Provencher L, Laberge F, et al. Comparative efficacy and safety of controlled­release morphinesuppositories and tablets in cancer pain. J Clin Pharmacol 1998; 38:74.

66. Bruera E, Fainsinger R, Spachynski K, et al. Clinical efficacy and safety of a novel controlled­releasemorphine suppository and subcutaneous morphine in cancer pain: a randomized evaluation. J Clin Oncol1995; 13:1520.

67. Eisele JH Jr, Grigsby EJ, Dea G. Clonazepam treatment of myoclonic contractions associated with high­dose opioids: case report. Pain 1992; 49:231.

68. Chu LF, Angst MS, Clark D. Opioid­induced hyperalgesia in humans: molecular mechanisms and clinicalconsiderations. Clin J Pain 2008; 24:479.

69. Arout CA, Edens E, Petrakis IL, Sofuoglu M. Targeting Opioid­Induced Hyperalgesia in Clinical Treatment:Neurobiological Considerations. CNS Drugs 2015; 29:465.

70. Low Y, Clarke CF, Huh BK. Opioid­induced hyperalgesia: a review of epidemiology, mechanisms andmanagement. Singapore Med J 2012; 53:357.

3/9/2016 Cancer pain management with opioids: Prevention and management of side effects

http://www.uptodate.com/contents/cancer­pain­management­with­opioids­prevention­and­management­of­side­effects?topicKey=PALC%2F2800&elapsedTi… 14/22

71. Chen L, Sein M, Vo T, et al. Clinical interpretation of opioid tolerance versus opioid­induced hyperalgesia. JOpioid Manag 2014; 10:383.

72. Eisenberg E, Suzan E, Pud D. Opioid­induced hyperalgesia (OIH): a real clinical problem or just anexperimental phenomenon? J Pain Symptom Manage 2015; 49:632.

73. Mao J, Sung B, Ji RR, Lim G. Chronic morphine induces downregulation of spinal glutamate transporters:implications in morphine tolerance and abnormal pain sensitivity. J Neurosci 2002; 22:8312.

74. Vanderah TW, Suenaga NM, Ossipov MH, et al. Tonic descending facilitation from the rostral ventromedialmedulla mediates opioid­induced abnormal pain and antinociceptive tolerance. J Neurosci 2001; 21:279.

75. Fishbain DA, Cole B, Lewis JE, et al. Do opioids induce hyperalgesia in humans? An evidence­basedstructured review. Pain Med 2009; 10:829.

76. Silverman SM. Opioid induced hyperalgesia: clinical implications for the pain practitioner. Pain Physician2009; 12:679.

77. Induru RR, Davis MP. Buprenorphine for neuropathic pain­­targeting hyperalgesia. Am J Hosp Palliat Care2009; 26:470.

78. Katz N, Mazer NA. The impact of opioids on the endocrine system. Clin J Pain 2009; 25:170.79. Rhodin A, Stridsberg M, Gordh T. Opioid endocrinopathy: a clinical problem in patients with chronic pain and

long­term oral opioid treatment. Clin J Pain 2010; 26:374.80. McWilliams K, Simmons C, Laird BJ, Fallon MT. A systematic review of opioid effects on the hypogonadal

axis of cancer patients. Support Care Cancer 2014; 22:1699.81. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 6th,

American Pain Society, Glenview, IL 2008.82. Fine P, Portenoy RK. Opioid analgesia. New York: McGraw Hill, 2004.

http://www.stoppain.org/pcd/content/forpros/opioidbook.asp (Accessed on April 21, 2011).83. Quigley C. Opioids in people with cancer­related pain. BMJ Clin Evid 2008; 2008.84. National Comprehensive Cancer Network (NCCN). NCCN Clinical practice guidelines in oncology.

http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on February 27, 2016).85. American Academy of Hospice and Palliative Medicine www.aahpm.org/certification/index.html (Accessed

on April 21, 2011).86. Ganesh A, Maxwell LG. Pathophysiology and management of opioid­induced pruritus. Drugs 2007; 67:2323.87. Hermens JM, Ebertz JM, Hanifin JM, Hirshman CA. Comparison of histamine release in human skin mast

cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology 1985; 62:124.88. Warner MA, Hosking MP, Gray JR, et al. Narcotic­induced histamine release: a comparison of morphine,

oxymorphone, and fentanyl infusions. J Cardiothorac Vasc Anesth 1991; 5:481.89. Ko MC, Song MS, Edwards T, et al. The role of central mu opioid receptors in opioid­induced itch in

primates. J Pharmacol Exp Ther 2004; 310:169.90. Zylicz Z, Smits C, Krajnik M. Paroxetine for pruritus in advanced cancer. J Pain Symptom Manage 1998;

16:121.91. Tarcatu D, Tamasdan C, Moryl N, Obbens E. Are we still scratching the surface? A case of intractable

pruritus following systemic opioid analgesia. J Opioid Manag 2007; 3:167.92. Friedman JD, Dello Buono FA. Opioid antagonists in the treatment of opioid­induced constipation and

pruritus. Ann Pharmacother 2001; 35:85.93. Yuan CS, Foss JF, O'Connor M, et al. Efficacy of orally administered methylnaltrexone in decreasing

subjective effects after intravenous morphine. Drug Alcohol Depend 1998; 52:161.94. Verhamme KM, Sturkenboom MC, Stricker BH, Bosch R. Drug­induced urinary retention: incidence,

management and prevention. Drug Saf 2008; 31:373.95. Chen YP, Chen SR, Pan HL. Systemic morphine inhibits dorsal horn projection neurons through spinal

cholinergic system independent of descending pathways. J Pharmacol Exp Ther 2005; 314:611.96. Meyboom RH, Brodie­Meijer CC, Diemont WL, van Puijenbroek EP. Bladder dysfunction during the use of

tramadol. Pharmacoepidemiol Drug Saf 1999; 8 Suppl 1:S63.97. Marret E, Kurdi O, Zufferey P, Bonnet F. Effects of nonsteroidal antiinflammatory drugs on patient­controlled

3/9/2016 Cancer pain management with opioids: Prevention and management of side effects

http://www.uptodate.com/contents/cancer­pain­management­with­opioids­prevention­and­management­of­side­effects?topicKey=PALC%2F2800&elapsedTi… 15/22

analgesia morphine side effects: meta­analysis of randomized controlled trials. Anesthesiology 2005;102:1249.

98. Rømsing J, Møiniche S, Mathiesen O, Dahl JB. Reduction of opioid­related adverse events using opioid­sparing analgesia with COX­2 inhibitors lacks documentation: a systematic review. Acta AnaesthesiolScand 2005; 49:133.

99. Wang J, Pennefather S, Russell G. Low­dose naloxone in the treatment of urinary retention during extraduralfentanyl causes excessive reversal of analgesia. Br J Anaesth 1998; 80:565.

100. Malinovsky JM, Lepage JY, Karam G, Pinaud M. Nalbuphine reverses urinary effects of epidural morphine: acase report. J Clin Anesth 2002; 14:535.

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GRAPHICS

Approved and commonly used drugs for chronic opioid inducedconstipation

Class Mechanism Use Problems

Bulk­forming laxatives(cellulose or psylliumseeds)

Increases mass andwater content of stool

Decreases transit time

Should always beconsidered; may beuseful in changingcharacter of theeffluent from afunctioning stoma

May worsenflatulence anddistentionShould be avoidedin patients who areseverely debilitatedor suspected ofearly bowelobstruction

Osmotic cathartics(magnesium salts,sodium salts,lactulose, sorbitol,polyethylene glycol)

Increases water in thebowel

Decreases transit time

Lactulose/sorbitolattracts water intocolon, acidifiescontents

Polyethylene glycolattracts water into thecolon

Often used for bowelcleansing beforemedical procedures

Lactulose and sorbitolhave a slower onsetand are commonlyselected for long­termuse; dose must beadjusted to effect

Polyethylene glycol isnot absorbed, has aslower onset, and thepowder formulationalso is commonly usedfor long­term therapy;dose must be adjustedto effect

Severe diarrheaand dehydrationmay occur withoveruseRarely, causesserious electrolytedisorders or volumeoverload

Patients with renalinsufficiency orcardiac failure mustbe carefullymonitored if sodiumor magnesium saltsare usedUse of phosphatecontaining laxativeshas been associatedwith acutephosphatenephropathy (rare);risk factors includechronic kidneydisease, frequentuse, and advancedageLactulose or sorbitolmay increaseflatulence

Lactulose should beavoided in patientswho are lactose­intolerant

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Surfactants (docusate) Facilitates mixture offat and stool

Usually combined witha contact cathartic asa first­line therapy foropioid­inducedconstipation

Minimal risks

Contact catharticsdiphenylmethanedrugs (bisacodyl)

Anthraquinone drugs(cascara, senna)

Increases peristalsis

Reduces absorption ofwater and electrolytesfrom intraluminalcontents

May be used for acuteor chronic therapy

Often a first­lineapproach for long­termmanagement,including prophylaxiswhen opioid therapy isinitiated

Risks associatedwith short term useare minimal"Laxative bowel", aconditioncharacterized bydependence onlaxatives for bowelfunction has beenreported but ispresumably rare

Allergies to thesesubstances havebeen reported

Opioid antagonists Opioid antagonist Goal is "bowelwithdrawal" withoutconcurrent systemicwithdrawal

Subcutaneousmethylnaltrexone

Opioid inducedconstipation inrefractory cases; doesnot cause systemicwithdrawal symptoms

Methylnaltrexonemust be givensubcutaneously;dosage adjustmentneeded for renalimpairment

Naloxegol Opioid inducedconstipation; does notcause systemicwithdrawal symptoms

Naloxegol ismetabolized byCYP3A4, numeroussignificant druginteractions areanticipatedDosage adjustmentneeded for renalimpairment

Oral naloxone Opioid inducedconstipation;parenteral formulationhas been given orally,but the optimal doseand schedule areunknown

Limited evidencesupporting efficacyof oral naloxoneand some patientswill absorbsufficient naloxoneto develop systemicwithdrawalsymptoms

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May causeabdominalcramping

Fixed combinationof extended­releaseoral oxycodone andnaloxone (2:1 ratio)

Chronic pain requiringaround­the­clockopioid treatment andprevention or relief ofopioid inducedconstipation

Exceeding themaximum dailydose of 80 mgoxycodone/40 mgnaloxone can causesystemicwithdrawalsymptomsThough systemicexposure of oralnaloxone is low(≤3%) amongpatients withnormal organfunction,bioavailabilityincreases in settingof hepaticimpairment and/orrenal impairment

Use iscontraindicated inmoderate to severehepatic impairmentNot recommendedfor perioperativeuse

Chloride channelactivator

Lubiprostone

Locally acting type 2chloride channel (ClC­2) activator

Treatment of opioidinduced constipation

Can cause nauseaand abdominal painSome patientsreport dyspneaand/or chesttightness within0.5­2 hours oftaking the drug(mechanismunknown)

Not studied inmethadone­associated OIC andbased upon in vitrodata provided in theproduct label; itmay not beeffective for that

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use

OIC: opioid induced constipation.

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Common strategies for managing opioid induced constipation

1. Non­pharmacologic approaches for all patients, unless contraindicated by medicalstatus

Increase fluid intake

Increase dietary soluble fiber (avoid if severely debilitated or bowel obstruction is suspected)

Encourage mobility

Ensure comfort and privacy for defecation

2. Select a pharmacologic strategy*

Intermittent use of a rectal therapy, either a suppository such as bisacodyl or glycerin or mineraloil and/or sodium phosphate enema

Intermittent use (every 2­3 days) of an osmotic laxative, such as polyethylene glycol,magnesium hydroxide, or magnesium citrate

Trial of a daily softening agent (docusate)

Intermittent use (every 2­3 days) of a contact cathartic, such as senna or bisacodyl

Daily use of a contact cathartic (with or without a concurrent softening agent)

Daily use of lactulose (unless lactose­intolerant) or sorbitol

Daily use of polyethylene glycol

3. Adjust dose and dosing schedule of selected therapy to optimize effects

4. Switch or combine conventional approaches if initial therapy is inadequate

5. Consider adding a peripheral opioid antagonist (eg, methylnaltrexone, naloxegol, oran opioid­naloxone fixed combination) or lubiprostone; if constipation continues to berefractory, consider alternative drugs, eg, metoclopramide.

*Fiber supplements and/or bulk forming laxatives (eg, psyllium) are an option for treating non­debilitatedpatients who maintain good oral hydration; however, efficacy is generally modest in patients with slowtransit constipation who are also more likely to experience bloating and distention. If used, patientsshould start with small amounts of fiber or bulking laxatives and increase gradually as tolerated.

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Anti­emetic drugs used to manage opioid­induced nausea

Class Mechanism Examples

Neuroleptics Dopamine receptor blockade in lower brainstem(chemoreceptor trigger zone)

Phenothiazines:

Prochlorperazine

Chlorpromazine

Butyrophenones:

Haloperidol

Atypical:

Olanzepine

Prokinetic drugs Peripheral effects to increase peristalsis; metaclopramidealso has central dopamine antagonist

Metoclopramide

5­HT3 receptorantagonists

Block serotonin receptor (chronic use may causeconstipation)

Palonosetron

Ondansetron

Granisetron

Dolasetron

Anticholinergicdrugs

Block acetylcholine release in lower brainstem Trimethobenzamide

Scopolamine

Promethazine

Antihistamines Block histamine receptors in lower brainstem Meclizine

Diphenhydramine

Dimenhydrinate

Hydroxyzine

Corticosteroids Multiple effects Dexamethasone

Benzodiazepines Reduce anxiety; direct effect on lower brainstem Lorazepam

Cannabinoids Binds to cannabinoid receptors to exert direct effect inthe lower brainstem

Dronabinol

Nabilone

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Disclosures: Russell K Portenoy, MD Grant/Research/Clinical Trial Support: Pfizer, Inc. [pain research grant to employer (morphine;oxycodone)]. Zankhana Mehta, MD Nothing to disclose. Ebtesam Ahmed, PharmD, MS Nothing to disclose. Janet Abrahm, MDSpeaker: Knowledge to Practice [Palliative care (I give talks and they charge a fee for the course)]. Other Financial Interest: JohnsHopkins University Press [Pain, palliative care, ethics, bone disease in cancer patients (I receive royalties from the three editions of thebook I wrote that they published­"A physician's guide to pain and symptom management in cancer patients")]. Diane MF Savarese, MDNothing to disclose.Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through amulti­level review process, and through requirements for references to be provided to support the content. Appropriately referencedcontent is required of all authors and must conform to UpToDate standards of evidence.Conflict of interest policy

Disclosures