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Prevention and management of side effects in patients receiving opioids for chronic pain

Prevention and management of side effects in patients receiving opioids for chronic pain
Authors:
Russell K Portenoy, MD
Zankhana Mehta, MD
Ebtesam Ahmed, PharmD, MS
Section Editor:
Janet Abrahm, MD
Deputy Editor:
Diane MF Savarese, MD
Literature review current through: Nov 2022. | This topic last updated: Nov 01, 2022.

INTRODUCTION — Opioids represent a mainstay for treatment of severe chronic pain in patients with active cancer or other serious chronic illnesses. Although the side effect liability of these drugs is significant and they are inherently associated with the serious problems of drug abuse and addiction, experience in the management of cancer pain indicates that they can potentially be used safely and effectively for all types of pain (ie, somatic, visceral, neuropathic). (See "Cancer pain management with opioids: Optimizing analgesia" and "Cancer pain management: General principles and risk management for patients receiving opioids".)

The term "chronic non-cancer pain" is ill defined but generally understood to apply to common types of musculoskeletal pain syndromes, such as arthritis and low back pain, and to headache. The long-term use of opioid drugs for these conditions is more controversial than use for cancer-related pain. For patients with chronic non-cancer pain, the decision to begin opioid therapy must be weighed carefully. (See "Use of opioids in the management of chronic non-cancer pain" and "Pharmacologic management of chronic non-cancer pain in adults", section on 'Opioids'.)

The public health consequences of opioid abuse drive the imperative that all clinicians assume responsibility for risk management when these drugs are prescribed for legitimate medical purposes. This applies to opioid use of any type in any population. (See "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'Risk assessment and management for patients receiving opioids' and "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis" and "Use of opioids in the management of chronic non-cancer pain", section on 'Evaluation of risk prior to initiating therapy'.)

Opioid therapy is associated with numerous side effects, the most common of which are gastrointestinal or neurologic. There is marked interindividual variability in the sensitivity to adverse effects from opioids, which may be due to genetic differences, age, comorbidity, or interactions with other drugs. The assessment and management of side effects is a best practice during opioid therapy. In many cases, however, a favorable balance between analgesia and side effects cannot be attained, a situation that may be termed "poor responsiveness." When a patient undergoing dose titration is determined be poorly responsive to a specific opioid, there are several approaches to consider: improving the symptomatic management of the dose-limiting side effect, changing to an alternative opioid (opioid rotation), or adding another therapy (a nonopioid analgesic, an adjuvant analgesic, or a nonpharmacologic treatment) that may improve analgesia even as the opioid dose is lowered.

This topic review will cover the prevention and management of specific adverse events in patients receiving chronic opioid therapy. Management of side effects in patients receiving opioid therapy for acute pain in the postoperative or acute critical illness settings is discussed elsewhere. (See "Pain control in the critically ill adult patient", section on 'Type and management of side effects'.)

OPIOID BOWEL DYSFUNCTION — It has long been recognized that opioids affect gastrointestinal motility. The usual effects include increased segmental motility and decreased peristalsis. The outcome usually is manifest as constipation. Motility disturbances and other opioid-related effects also may lead to nausea, bloating, early satiety, or pain. Occasionally, patients develop ileus or a syndrome characterized by a relatively high level of abdominal pain, a condition that has been termed "narcotic bowel syndrome" [1]. Theoretically, the pain in this condition may be related to an interaction between increased nonpropulsive motility and visceral hyperalgesia, such as what occurs in functional gastrointestinal disorders. If the phenomenon of visceral hyperalgesia is occurring, it could, in turn, be related to the phenomenon of opioid-induced hyperalgesia. However, there is no direct evidence to support the latter pathophysiology. (See 'Opioid-induced hyperalgesia' below.)

Constipation — In opioid-treated cancer patients, the prevalence of constipation can be as high as 60 to 90 percent, and for clinical purposes, it is assumed that the opioid plays an important role irrespective of other contributory factors [2]. Constipation can significantly impact quality of life, as well as opioid use patterns, resource utilization, and costs [3,4].

Contributory factors — Multiple factors contribute to the development of opioid-induced constipation (OIC) in patients receiving systemic opioids:

Opioids bind to specific receptors in the gastrointestinal tract and central nervous system to reduce peristalsis.

Longer gastrointestinal transit time causes excessive water and electrolyte reabsorption from feces, and decreased 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 vinca alkaloids), and tumor-related bowel obstruction may also contribute. (See "Chemotherapy-associated diarrhea, constipation and intestinal perforation: pathogenesis, risk factors, and clinical presentation", section on 'Constipation' and "Palliative care of bowel obstruction in cancer patients".)

Not all opioid formulations are equally constipating. Although the results of randomized trials are conflicting [5-8], two systematic reviews of patients receiving opioids for cancer and non-cancer pain concluded that there is less constipation with transdermal fentanyl than with oral sustained-release morphine [9,10]. There have been no direct comparisons of the constipating effects of these drugs, and in the absence of anecdotal reports of differential effects on the gut, the explanation for these observations has focused on the route of administration. The non-oral route presumably impacts opioid receptors less than the oral route and, for this reason, may be less constipating. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'Fentanyl'.)

In addition, a combined preparation of long-acting oxycodone and naloxone in a fixed 2:1 ratio is available in some countries and is associated with less constipation, and no compromise in analgesic efficacy (in the approved dose range) or safety compared with an equivalent dose of oxycodone alone [11]. (See 'Other orally administered opioid antagonists' below.)

Diagnosis — The diagnosis of OIC should be based upon clinical history, appropriate physical examination (including a rectal examination, unless not indicated), and limited diagnostic tests. Diagnostic criteria for OIC are available (the ROME-IV criteria) [12]:

New or worsening symptoms of constipation when initiating, changing, or increasing opioid therapy, which must include two or more of the following:

Straining during more than one-fourth of defecations

Lumpy or hard stools in more than one-fourth of defecations

Sensation of incomplete evacuation in more than one-fourth of defecations

Sensation of anorectal obstruction/blockage in more than one-fourth of defecations

Manual maneuvers to facilitate more than one-fourth of defecations (eg, digital evacuation, support of the pelvic floor)

Fewer than three spontaneous bowel movements per week

Rarely, severe OIC can produce obstipation with postobstructive diarrhea

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 be undertaken. The physical examination should be focused to determine if an organic problem exists to account for symptoms [12]. A careful anorectal examination can identify structural issues and fecal impaction.

Few data are available regarding the clinical utility of tests in suspected OIC. If clinically indicated, simple laboratory tests (eg, complete blood count, serum calcium, thyroid-stimulating hormone) are reasonable, as hypercalcemia and hypothyroidism may contribute to constipation. An abdominal plain radiograph can identify fecal impaction and the level of stool burden. Occasionally, colonoscopy is indicated to assess a possible coexisting intraluminal lesion. Potentially remediable contributors to constipation should be managed appropriately.

Prevention — Prevention is the preferred strategy. All patients with predisposing factors (eg, advanced age, immobility, poor diet, intra-abdominal pathology, neuropathy, hypercalcemia, concurrent use of other constipating drugs) should be considered for prophylactic laxative therapy when opioid treatment is initiated. Conventionally, this is accomplished using either a contact cathartic (eg, senna, two tablets at bedtime to start), an osmotic laxative (eg, polyethylene glycol, lactulose, or magnesium sulfate), or both. There are many options. Some patients may have previously tried a contact cathartic and do not favor this approach because of abdominal cramping. They can be treated with a daily dose of an osmotic laxative (eg, polyethylene glycol [PEG] 17 g [one heaping tablespoon] or lactulose [30 mL]). Yet, other patients tolerate the contact cathartic but benefit from as-needed administration of the osmotic laxative (eg, PEG 17 g [one heaping tablespoon] or lactulose [30 mL] as needed). In general, we would avoid use of lactulose in lactose-intolerant patients. Finally, some patients are troubled by hard and dry stools, and for this problem, the surfactant docusate can be added on a daily basis to the contact cathartic. All patients should be encouraged to increase fluid intake and mobility; the intake of soluble dietary fiber also should be increased unless the patient is debilitated, has limited oral fluid intake, or bowel obstruction is suspected. In addition, comfort and privacy for defecation must be ensured (table 1). Use of a squatting posture can improve defecation as it is thought to straighten the anorectal angle to reduce straining [13]. Devices to promote a squatting or semi-squatting position are commercially available [14].

Initial management — The following reflects our approach to initial management:

For patients who are at increased risk of OIC or develop OIC, we suggest starting with conventional laxatives as first-line agents. The choice of agent and the dosing are empiric. Although one small randomized trial suggested that sennosides were as effective as, but less expensive than, lactulose [15]; there are no adequately powered randomized trials comparing sennosides, lactulose, or PEG [16].

If a patient is tolerating conventional laxative therapy, but it has been insufficiently effective, dose escalation should be considered. The contact cathartic dose can be doubled or tripled unless the patient develops abdominal cramping or diarrhea. The dose of an osmotic laxative can be increased (given once or twice daily) until diarrhea occurs, then the dose is lowered. Alternatively, a patient whose preventative regimen is ineffective can be switched to a different conventional laxative strategy (eg, from a contact cathartic to an osmotic cathartic, or vice versa) (table 1). We would avoid use of lactulose in lactose-intolerant patients, and we restrict use of a stool softener, such as docusate, to patients who describe hard, dry stools.

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

Some patients also are able to improve bowel function through dietary modifications (increased consumption of fluids and soluble dietary fiber) and increased physical activity. Fiber should not be increased if the patient is debilitated, fluid intake is limited, or bowel obstruction is suspected.

Regular ingestion of probiotics can improve chronic constipation; given the safety of these therapies, a trial in patients with OIC is reasonable. (See 'Other therapies' below.)

The use of conventional laxative therapy is recommended based on extensive experience; there continues to be limited high-quality evidence of efficacy for OIC

[16-20]. There is evidence of benefit in chronic idiopathic constipation; however, in a systematic review and meta-analysis from 2011 examining the efficacy of laxatives in chronic idiopathic constipation [21], the authors identified seven randomized controlled trials evaluating 1411 patients (laxatives, n = 876; placebo, n = 535) treated with stimulant or osmotic laxatives; laxatives were found to be superior to placebo for spontaneous bowel movement response (pooled risk ratio [RR] 2.24, 95% CI 1.93-2.61) and change in bowel movement frequency (mean difference between the laxative and placebo groups was an increase of 2.55 [1.53 more to 3.57 more]). Laxatives were also associated with a reduction in straining (RR 1.52, 95% CI 1.18-1.96), an improvement in stool consistency, and a reduction in passage of hard stools (RR 1.55, 95% CI 1.33-1.82). (See "Management of chronic constipation in adults", section on 'Other laxatives' and "Bowel preparation before colonoscopy in adults".)

There are numerous options for conventional laxative therapy (table 2) and no data to suggest that any one approach is superior to any other. In a Cochrane systematic review of management of OIC in a population with advanced illness, four randomized trials comparing different kinds of laxatives showed no significant differences among them [22]. The specific approach selected should be consistent with patient preference (table 1). For patients who are lactose intolerant, lactulose may cause excessive gas and abdominal pain, cramping, and bloating; it should be avoided in these patients [23].

Previously, it was common to use a stool softener in conjunction with a laxative, but studies now suggest that it need not be included:

There is little evidence to support the use of surfactant agents in chronic constipation. Stool softeners, such as docusate sodium, are intended to lower the surface tension of stool, thereby allowing water to more easily enter the stool. Although these agents have few side effects, they are less effective than other laxatives [24]. (See "Management of chronic constipation in adults", section on 'Surfactants'.)

There was no significant benefit of docusate plus sennosides compared with placebo plus sennosides in managing constipation in a randomized trial conducted in 74 hospice patients; over 95 percent of the enrolled patients received opioids during each of the 10 days of the trial [25].

Given these limited observations, it would be reasonable to individualize the use of a stool softener, such as docusate, and use it when patients describe hard, dry stools. In practice, clinicians often simply coadminister docusate and a contact cathartic, such as senna, as a first-line approach to constipation, without regard for the presence of specific indications for the surfactant.

Management of refractory opioid-induced constipation — When conventional approaches are insufficiently effective, strategies that are used in refractory situations should be considered. For refractory cases of OIC, there are numerous approaches (table 2), including opioid receptor antagonist therapy and lubiprostone, which are specifically approved for this indication. Although many of these drugs, including lubiprostone, have not been tested directly in cancer patients, and their US Food and Drug Administration (FDA) approvals are for OIC in patients with noncancer pain, they are used in refractory OIC in patients with cancer.

In general, we prefer a peripherally acting mu-opioid receptor antagonist (PAMORA) for most patients. The choice of agent is empiric, as there are no high quality trials directly comparing any of the available agents [26]. For most patients, we suggest methylnaltrexone. If an oral agent is preferred, options include naloxegol, oral methylnaltrexone, or where available, naldemedine.

Consensus-based recommendations for the use of prescription drugs for OIC are available from the American Gastroenterological Association (AGA) [27]. These guidelines, which recommend use of the Bowel Function Index (BFI) to evaluate OIC (table 3) [28], suggest that prescription therapies be considered for a score of ≥30 points in patients with previous or current use of first-line interventions (laxatives, stool softeners, bulk agents). However, in the clinical setting, the decision to proceed to a trial of a prescription drug for OIC is more typically based on a broader assessment, which may include factors as varied as the patient’s level of constipation-associated distress, psychologic reaction to the possibility of another over-the-counter strategy, and extent of insurance coverage for the cost of prescription medications. Given the large number of over-the-counter treatments, which may be tried in combination and at varied doses, the decision to label the patient’s symptoms as "refractory" and proceed to a prescription-based approach is ultimately determined through discussion with the patient about the burdens, risks, and costs associated with the next trial.

Opioid antagonists — We suggest peripherally acting mu-opioid receptor antagonists (PAMORAs) for refractory OIC in the absence of bowel obstruction. These agents should be avoided in the presence of bowel obstruction.

The benefit of PAMORAs as a group for treatment of refractory OIC in patients with cancer or another advanced illness has been addressed in the following meta-analyses:

A year 2022 Cochrane review summarized results from ten trials, totaling 1343 adults with cancer irrespective of stage or at a palliative care stage of any disease [29]. There were two trials of oral naldemedine, three of naloxone in combination with oxycodone, one of naloxone alone, and four of subcutaneous methylnaltrexone. The following conclusions were reached:

All trials were vulnerable to bias, mostly because of a high risk of detection bias due to nonblinded outcome assessment.

There was moderate-certainty evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIC (two trials, 418 participants, RR 2.00, 95% CI 1.59-2.52), and there was very-low-certainty evidence that naldemedine had no effect on opioid withdrawal (one trial, 112 participants). However, naldemedine increased the risk of adverse events (two studies, 418 patients, RR 1.49, 95% CI 1.19-1.87, moderate-quality evidence), the most common of which was diarrhea.

The data were insufficient to judge the benefits and risks of naloxone alone compared with placebo (one crossover trial, 17 patients). There was low-certainty evidence that oxycodone/naloxone had no effect on analgesia. No trial evaluated laxation response of combined therapy over the first two weeks of administration. There was very-low-certainty evidence that oxycodone/naloxone did not increase the risk of serious adverse events, and there was low-certainty evidence that it did not increase the risk of any adverse events.

Methylnaltrexone improved bowel function, with more spontaneous laxations within 24 hours (two studies, 287 patients, RR 2.97, 95% CI 2.13-4.13, low-certainty evidence), and over two weeks (two studies, 305 patients, RR 8.15, 95% CI 4.76-13.95], moderate-certainty evidence) in people receiving palliative care. Methylnaltrexone also increased the proportion of patients reporting improved bowel status at the end of the trial (2 studies, 287 patients, RR 2.32, 95% CI 1.64-3.27, low-certainty evidence). There was low-certainty evidence that the rate of opioid withdrawal was not affected by methylnaltrexone, and low-certainty evidence that it increased adverse events (three studies, 518 patients, RR 1.17, 95% CI 1.05-1.30). There was little to no difference in risk of spontaneous laxations or in patient assessment of improved bowel status, or in symptoms of opioid withdrawal with lower versus higher doses of methylnaltrexone (1 versus ≥5 mg subcutaneously).

A separate meta-analysis evaluated 23 placebo-controlled trials of PAMORAs, and concluded that methylnaltrexone, naldemedine, naloxegol, and naloxone were all superior to placebo, with a RR of failure to respond to therapy of 0.63 (95% CI 0.56-0.71) for naloxone (five trials, 838 participants, moderate-certainty evidence), 0.65 (95% CI 0.52-0.82) for naldemedine (four trials, 1525 participants, moderate-certainty evidence), 0.77 (95% CI 0.61-0.97) for naloxegol (three trials, 1522 participants, moderate-quality evidence), 0.68 (95% CI 0.58-0.80) for alvimopan (four trials, 1579 participants, moderate-certainty evidence), and 0.62 (95% CI 0.50-0.76) for methylnaltrexone (six trials, 1622 participants, high-quality evidence).

The following sections will review the data for individual agents.

Methylnaltrexone — Methylnaltrexone is a PAMORA, and like other drugs in this class it has a restricted ability to cross the blood brain barrier. It does not induce symptoms of opioid withdrawal. In the United States, subcutaneous methylnaltrexone is approved for OIC in patients with chronic non-cancer pain and for patients with any advanced illness receiving palliative care who have had an inadequate response to traditional laxatives. Oral methylnaltrexone (450 mg once daily) is approved for OIC in patients with chronic non-cancer pain; it can be used off-label for patients with cancer and OIC.

The efficacy of subcutaneous methylnaltrexone for the treatment of OIC has been shown in multiple randomized trials and confirmed in several meta-analyses [22,30-32]. In a network analysis of 21 randomized controlled trials evaluating drugs used in OIC, subcutaneous methylnaltrexone was significantly better at reversing OIC than lubiprostone, naloxegol, oral methylnaltrexone, and prucalopride (a highly selective 5-hydroxytryptamine type 4 [5HT4] receptor agonist that acts as a prokinetic in the gut) [31,33].

When used chronically, methylnaltrexone may be given subcutaneously once every other day or every third day; the frequency of administration can be increased, if needed, but should not exceed once daily. The approved dose of the injectable formulation is 8 mg for patients weighing 38 to 61 kg and 12 mg for those weighing 62 to 114 kg; for those outside these ranges, the recommended dose is 0.15 mg/kg. Long-term administration of methylnaltrexone is effective and safe [34,35].

Higher doses may provide additional benefit, although the data are limited. In the trial described above, a subgroup of 41 patients received dose escalation during the second week of therapy because of limited effectiveness (20 in the methylnaltrexone group, 21 in the placebo group at an equivalent volume) [36]. The fraction of patients who had a bowel movement within four hours of increasing the methylnaltrexone dose to 0.3 mg/kg was 24 percent (compared with 15 percent within four hours of the prior dose of 0.15 mg/kg). The corresponding rates in the placebo group were 8 percent before and 7 percent after dose escalation. The pattern of adverse events in patients who had dose escalation did not differ in either group.

Although less data are available, the available evidence also suggests that oral methylnaltrexone is effective and well tolerated for treatment of OIC without adversely impacting analgesia, at least in patients with chronic non-cancer pain [37-39].

Concerns have been raised about severe abdominal pain and bowel perforation in patients with advanced cancer who were receiving methylnaltrexone for OIC [40-42]. These concerns led the FDA to issue a warning for clinicians to use caution when administering methylnaltrexone to patients with known or suspected lesions in the intestinal wall, and to stop the drug immediately for worsening of gastrointestinal symptoms [43].

Naloxegol — Naloxegol, a pegylated form of naloxone, appears to be effective against refractory OIC in patients with non-cancer-related pain, without reversal of the analgesic effect; benefit in patients with chronic non-cancer pain is supported by one phase 2 trial and two randomized placebo-controlled phase 3 trials [44,45]. A single prospective nonrandomized study in 124 patients with cancer pain and OIC supports efficacy and safety in those with an inadequate response to laxative therapy [46]. In the United States, naloxegol is approved for treatment of OIC in patients with non-cancer pain. It can be used off-label in the cancer population. The European Medicines Agency (EMA) has approved naloxegol for treatment of OIC without the restriction to non-cancer pain.

As has been seen with methylnaltrexone, cases of gastrointestinal perforation have been reported with naloxegol [47].

Naldemedine — Naldemedine is an orally active PAMORA. Benefit for OIC was shown in two identically designed, double-blind, placebo-controlled, 12-week phase III trials conducted in patents with non-cancer chronic pain and OIC (COMPOSE 1 and 2) [48]. Responders were defined as those with 9 or more positive response weeks (PRW) out of 12 and three PRW of the last four weeks. A PRW was defined as three or more spontaneous bowel movements per week and an increase of one or more spontaneous bowel movements per week over baseline. COMPOSE 1 enrolled 547 subjects, 274 to naldemedine (0.2 mg orally daily) and 273 to placebo, while COMPOSE 2 enrolled 553 individuals, 277 to the same dose of naldemedine and 276 to placebo. There was a significantly greater proportion of responders with naldemedine (study I, 47.6 versus 34.6 percent; study II, 52.5 versus 33.6 percent). A significantly greater increase in the frequency of spontaneous bowel movements per week from baseline was noted with naldemedine during week 1, and the difference between the two groups persisted throughout the 12-week study period. In both studies, treatment with naldemedine was well tolerated; the only treatment-emergent adverse effects with incidence >5 percent with naldemedine were abdominal pain (17 versus 5 percent with placebo in study I) and diarrhea (18 versus 8 percent with placebo in study I). Naldemedine was not associated with signs or symptoms of opioid withdrawal, and the analgesic effect of the opioid was not significantly affected. Subsequently, two additional randomized controlled trials in patients with chronic non-cancer pain came to similar conclusions [49,50].

Largely based on the experience from COMPOSE 1 and 2, naldemedine was approved in the United States for OIC in adult patients with chronic non-cancer pain [51]. However, efficacy was also shown for naldemedine in the treatment of OIC in patients with cancer in a randomized, placebo-controlled, phase III trial (71 percent responded to 0.2 mg/day compared with 34 percent of the placebo group, using the same response criteria as used in the COMPOSE trials) [52], and the drug can be used off-label in the cancer population. The EMA has approved naldemedine for treatment of OIC without the restriction to non-cancer pain [53].

Alvimopan — Alvimopan is an orally administered PAMORA that is approved in the United States for short-term inpatient management of postoperative ileus in patients undergoing bowel resection. (See "Postoperative ileus" and "Measures to prevent prolonged postoperative ileus", section on 'Peripheral acting mu-opioid receptor antagonists'.)

The benefit of alvimopan for OIC was shown in a meta-analysis of four randomized trials (1693 patients, all with non-cancer-related pain [54-57]) in which the relative risk (RR) for continued constipation with alvimopan was 0.71 (95% CI 0.65-0.78) [30]. In one of the trials, active treatment did not increase the requirement for opioid medication or increase pain intensity scores [56]. The drug was specifically not approved for OIC because an earlier unpublished 12-month safety study in patients treated with opioids for chronic pain had shown more reports of myocardial infarction in patients treated with alvimopan than with placebo [58]. Although a causal relationship has not been established, without more information, the use of this drug in the ambulatory setting for OIC in cancer patients cannot be recommended.

Other orally administered opioid antagonists — Other orally administered opioid antagonists are also available for treatment of refractory OIC.

Oral naloxone (1 to 12 mg), an opioid antagonist, has been used to treat OIC; in a meta-analysis of four placebo-controlled randomized trials (798 patients, predominantly receiving opioids for non-cancer-related pain [59-62]), the RR for continued constipation was significantly lower with naloxone (RR 0.64, 95% CI 0.56-0.78) [30]. However, it is 3 percent bioavailable [63] with oral administration and, for this reason, may reverse systemic opioid effects, potentially worsening pain or inducing withdrawal effects.

A new naloxone sustained-release capsule appears to be safe and efficacious for the treatment of OIC without compromising the desired opioid analgesic effects [64]. However, this formulation is not available or approved in any country as of yet.

A fixed-ratio combination of immediate-release oxycodone plus naloxone is available commercially (Targin and Targinact) in Germany, Canada, and some other countries. A long-acting formulation of oxycodone plus naloxone (Targiniq ER) is approved in the United States for treatment of moderate to severe pain for which alternative treatment options are inadequate [11,59]. Although this drug combination has no labeled indication for relief or prevention of OIC in the United States, some countries, such as Canada, have approved the fixed-dose combination for treatment of chronic pain and relief or prevention of OIC in patients who require an opioid. This approval is based on randomized studies demonstrating that in patients with chronic non-malignant pain, oxycodone/naloxone results in better intermediate-term bowel function compared with oxycodone or morphine alone while maintaining pain relief [65].

Lubiprostone — Lubiprostone is a type-2 chloride channel activator that induces secretion of fluid in the intestine. Efficacy in OIC has been confirmed in at least three randomized controlled trials [66,67]. In the largest of these trials, 418 patients with chronic non-cancer pain and OIC were randomly assigned to lubiprostone (24 mcg twice daily) or placebo for 12 weeks [66]. Patients receiving lubiprostone had significant improvement in spontaneous bowel movements, abdominal discomfort, straining, constipation severity, and stool consistency. Patients rated lubiprostone effectiveness to be higher than placebo during 11 of the 12 weeks, and side effects were largely tolerable (nausea, lubiprostone 17 versus 6 percent with placebo; diarrhea, 10 versus 3 percent; and abdominal distention, 8 versus 2 percent).

On the other hand, efficacy for lubiprostone could not be shown in a third identically designed phase III trial of 451 patients with chronic non-cancer pain [68]. The authors performed a pooled analysis of all three trials and concluded that the efficacy of lubiprostone for OIC might be limited to patients receiving non-methadone opioids.

In the United States, lubiprostone is approved for treatment of OIC in patients receiving opioid therapy for chronic non-cancer pain, including patients with chronic pain related to prior cancer or its treatment who do not require frequent (ie, weekly) opioid dose escalation.

Other therapies — Small, randomized, placebo-controlled trials of probiotics in patients with chronic constipation without irritable bowel syndrome and in normal subjects with a tendency toward infrequent stools suggest improvement in defecation frequency and stool consistency [69]. However, a systematic review concluded that until larger studies are performed, there are insufficient data to recommend probiotics in the management of severe constipation [70]. Nevertheless, given the relative safety of these therapies, a trial in patients with OIC would not be unreasonable [71]. (See "Probiotics for gastrointestinal diseases", section on 'Constipation'.)

Linaclotide, a guanylyl cyclase C agonist, is approved for the treatment of irritable bowel syndrome and chronic idiopathic constipation. It could be considered for a trial in those with OIC. (See "Management of chronic constipation in adults", section on 'Linaclotide'.)

In addition, prucalopride, a highly selective 5HT4 receptor agonist that acts as a prokinetic in the gut, is approved for treatment of chronic idiopathic constipation; it too may be considered for a trial in those with OIC. (See "Management of chronic constipation in adults", section on 'Prucalopride'.)

Guidelines from expert groups — A 2019 guideline on management of OIC is available from the AGA [27]:

Traditional laxatives should be used as first-line agents.

PAMORAs should be considered only when traditional laxatives fail.

The committee offered a strong recommendation based on a moderately strong to strong quality of evidence for use of naloxegol and naldemedine, but it offered only a conditional recommendation based on only a low quality of evidence for use of methylnaltrexone. They also pointed out that the costs of naloxegol and naldemedine are substantially lower than that of methylnaltrexone. The committee noted that only two of the five reviewed randomized trials of methylnaltrexone were conducted in non-cancer patients, and they did not review the multiple meta-analyses and network analyses reported above.

There is insufficient evidence to support the use of lubiprostone or prucalopride for the management of OIC.

Recommendations have also been proposed by the American Academy of Pain Medicine (AAPM) [72], the Multinational Association for Supportive Care in Cancer (MASCC) [73], and the European Society for Medical Oncology (ESMO) [74]. The MASCC recommendations do not specify which PAMORA is preferred, and they also support the use of alternative agents, such as linaclotide, lubiprostone, or prucalopride, in patients who fail to respond to first-line conventional laxatives [73].

Narcotic bowel syndrome — Narcotic bowel syndrome is a type of opioid-induced bowel dysfunction that is characterized by the seemingly paradoxical development of worsening abdominal pain in the context of escalating or continuous chronic opioid therapy [75]. It is most often described in patients taking opioids for chronic non-cancer pain and in opioid misusers [76-78].

The underlying pathophysiologic mechanisms are incompletely understood, although centrally mediated opioid-induced hyperalgesia may contribute [79]. (See 'Opioid-induced hyperalgesia' below.)

When a patient who is receiving long-term opioid therapy and has OIC develops abdominal pain, the usual response is to reevaluate the patient for a potentially treatable cause of the pain and modify the laxative regimen. Sometimes, the opioid dose is increased. The term "narcotic bowel syndrome" becomes diagnostically useful if no alternative cause is found and if changes in the laxative regimen are not helpful (or paradoxically increase cramping), particularly if pain increased in tandem with an increase in opioid dose.

When the diagnosis of narcotic bowel syndrome is appropriate, opioid tapering must be considered [80]. A cornerstone of management is the development of a therapeutic alliance with the patient in the context of symptom validation, detailed education, and mutual agreement on symptom reduction goals, with the ultimate aim of opioid detoxification [75]. Proposed treatments include early incorporation of nonpharmacologic therapies (eg, stress reduction, exercise), opioid-sparing analgesics (eg, antidepressants), laxatives to control transient constipation, and referral for psychologic support. Opioid rotation is often considered as well.

SOMNOLENCE AND MENTAL CLOUDING — Opioid therapy can cause somnolence or mental clouding. Typically, sedation is most problematic upon dose initiation or escalation, and most patients develop tolerance within days to weeks. Symptoms are persistent in some patients, particularly in those with other contributing factors such as early dementia or the use of other centrally acting drugs, particularly benzodiazepines. Concurrent use of benzodiazepines and gabapentinoids increases the risk for oversedation, respiratory depression, and death. (See 'Respiratory depression' below.)

The characteristics of opioid-induced somnolence and mental clouding can vary widely. The degree of cognitive impairment 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 and hypnagogic illusions to frank hallucinations, can occur, as can mood disturbances. In this population, mood disturbance is more often negative (irritability, depressed mood, dysphoria) than positive (contentment, euphoria).

The incidence of cognitive dysfunction in patients receiving chronic opioid therapy is not well characterized. A prospective, multicenter, cross-sectional study of 1915 adult patients with cancer who received opioids for at least three days suggested that possible or definite cognitive dysfunction (as assessed by Mini-Mental State Examination [MMSE]) scores lower than 27 were present in one-third of treated patients [81]. Risk factors for cognitive dysfunction included a diagnosis of lung cancer, daily opioid doses (oral morphine equivalents) of ≥400 mg, older age, low performance status (table 4), and time since cancer diagnosis <15 months; the presence of breakthrough pain was associated with better cognitive function. (See "The mental status examination in adults", section on 'Cognitive screening tests'.)

Evaluation — Like other symptoms associated with opioid therapy, the decision to pursue additional evaluation is a clinical judgment that is influenced by the likelihood that other factors may be contributing. If the relationship of the symptoms to the drug or other factors is clear, further evaluation may not be needed. (See "Diagnosis of delirium and confusional states".)

Overdose versus side effect — Evaluation of the severity and temporal course of the somnolence or cognitive change is important whether or not the opioid is the primary factor responsible for the symptoms and signs or one of several factors. A rapidly evolving decline in consciousness or cognition, or presentation when the symptoms or signs are severe increases the urgency of intervention. Depending on the circumstances, evolving opioid overdose must be considered, which in turn necessitates continuous observation, rapid evaluation for other causes, and consideration of antagonist therapy with naloxone should hypoventilation be observed or appear to be imminent. Clinical decisions in this situation rely on the history of opioid consumption and the assessment of somnolence and respiratory pattern; there are no other signs of opioid excess reliable enough to use as an indicator that the opioid is or is not a primary determinant of the condition. Naloxone should not be used unless there is respiratory compromise, and it is important to understand that the clinical improvement that may occur when a symptomatic patient receiving an opioid is given naloxone does not mean that the opioid is the sole factor, or even the major factor, responsible for the patient’s cognitive changes. (See "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis", section on 'Overdose and mortality'.)

If the patient’s somnolence or change in cognition is rapidly evolving but the respiratory pattern is normal, continuous observation may be necessary, and the opioid should be held until there is greater certainty about the diagnosis and the patient has stabilized. If the opioid is determined to be responsible for this occurrence, the decision to restart therapy should incorporate more cautious dosing and increased monitoring.

Most patients who experience the side effect of somnolence or cognitive impairment have relatively mild, and slowly evolving or stable symptoms. Evaluation and management in this situation typically occur in the ambulatory environment and do not require the use of naloxone.

Management — A stepwise approach to management of opioid-induced somnolence and mental clouding includes the following:

Obvious contributing causes (eg, primary CNS pathology, metabolic disturbances, dehydration, other drugs) should be addressed and treated if this is feasible and consistent with the goals of care. Nonessential centrally acting medications, especially CNS depressants, should be reduced or eliminated.

The opioid regimen should be evaluated. If analgesia is satisfactory, it may be possible to reduce the dose, but this is often limited by worsened pain. The impact of an empiric 25 percent dose reduction on 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 opioid-sparing effect. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'Pain that respond poorly to opioids alone' and "Cancer pain management: Role of adjuvant analgesics (coanalgesics)" and "Cancer pain management: Use of acetaminophen and nonsteroidal anti-inflammatory drugs".)

Drug treatment directed at the symptom (ie, a psychostimulant) may be considered.

Psychostimulants — The potential value of a CNS stimulant to mitigate opioid-induced somnolence or mental clouding is suggested by limited clinical literature and anecdotal experience [82,83]. The largest experience is with methylphenidate for patients with cancer pain and with modafinil for patients receiving opioids for non-malignant pain.

Methylphenidate – Benefit for methylphenidate in patients receiving opioids has been suggested in two of three small randomized trials, all of which were conducted in patients with cancer pain [84-86]. A systematic review concluded that this represented weak evidence in support of the use of methylphenidate given that the quality of the negative study was lower than that of the two positive studies [87]. Notably, treatment with methylphenidate may be 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 comparable dose of one of the long-acting modified-release formulations. The dose usually requires titration until benefits occur or side effects supervene [88]. Most patients experience benefit at doses well below 60 mg/day, but some require higher doses.

ModafinilModafinil, a nonamphetamine psychostimulant, appears to cause fewer sympathomimetic side effects than methylphenidate and other psychostimulants. Evidence to support benefit of modafinil to prevent opioid-induced sedation is limited to retrospective reports of patients with pain of non-malignant origin [89-91].

Modafinil is initiated at 100 to 200 mg/day and may require dose escalation to optimize effects. Most patients require no more than 600 mg/day, and only occasional patients require twice daily, as compared with once daily, dosing.

Other psychostimulants and cholinesterase inhibitors – Other psychostimulants that may be beneficial in the setting of opioid-induced sedation include dextroamphetamine [92], dexmethylphenidate, armodafinil, atomoxetine, and caffeine [93]. An alternative approach, the use of a cholinesterase inhibitor, donepezil, also has been studied but the data are very limited [94,95]. A systematic review of treatment for opioid-related CNS symptoms concluded that the quality of the studies involving dextroamphetamine, caffeine, and donepezil was not sufficient to make any recommendations about their use [87]. These drugs are usually considered only if methylphenidate or modafinil are poorly tolerated or contraindicated.

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

All psychostimulants can produce side effects such as tremulousness, insomnia, anorexia, anxiety, tachycardia, and hypertension. Given the potential for these adverse effects, relative contraindications to the use of psychostimulants include severe insomnia, a psychiatric disorder characterized by anxiety or paranoid ideation, significant cardiac disease, or poorly controlled hypertension. Older patients and those with early dementing illnesses are especially susceptible to untoward psychotomimetic and cognitive disturbance.

While the available data suggest that the risk of serious cardiovascular problems with psychostimulants is low in adults treated for attention-deficit hyperactivity disorder [96], there are no data on their safety in patients with preexisting arrhythmias, such as stable controlled atrial fibrillation. Consultation with the patient’s cardiologist is advised in such cases to determine whether the findings are sufficiently severe to avoid use of these medications. The cardiovascular effects of psychostimulants in adults are discussed in detail elsewhere. (See "Management of attention deficit hyperactivity disorder in adults", section on 'Adverse effects'.)

Opioid-induced delirium — Opioids can contribute to the onset or persistence of delirium. Typically, the opioid is one of several factors that may be etiologically important. Other centrally acting drugs may be involved and worsen delirium through a direct effect (eg, glucocorticoid) or through an effect that augments anti-anticholinergic load. Metabolic disturbances causes by major organ dysfunction or other factors, such as dehydration, also are commonly encountered. If the opioid is perceived as contributing, management may include a trial of a lower dose (eg, dose reduction of 25 to 50 percent) to determine whether this change is associated with worsening pain, a switch to an alternative opioid (ie, opioid rotation), and/or treatment of symptoms with a co-administered neuroleptic.

In general, clinicians must balance the benefits of using opioids to treat significant pain with the potential for development of opioid-related delirium, as discussed in detail elsewhere. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis".)

OTHER SIDE EFFECTS — Numerous other side effects are less common but widely recognized opioid-related problems. This section does not address issues related to opioid abuse, including overdose. (See "Prescription drug misuse: Epidemiology, prevention, identification, and management", section on 'Opioid analgesics' and "Opioid use disorder: Epidemiology, pharmacology, clinical manifestations, course, screening, assessment, and diagnosis", section on 'Overdose and mortality'.)

Nausea and vomiting — Nausea frequently complicates the initiation of opioid therapy, but tolerance occurs quickly, and persistent nausea is infrequent. When persistent nausea occurs, it is often in the context of other, less well-characterized gastrointestinal symptoms, including dry mouth, reflux, anorexia, early satiety, and abdominal bloating [97].

Based upon clinical observations, there is much individual variation in the occurrence of nausea and in the response of the individual to different opioid drugs. One patient may experience intense nausea with morphine and none while receiving hydromorphone, while the opposite may be observed in a different patient. There have been no comparative studies among the commonly used mu-agonist opioids.

Opioids have three potentially emetogenic mechanisms: a direct effect on the chemoreceptor trigger zone, enhanced vestibular sensitivity, and delayed gastric emptying [98]. Refractory constipation and stool impaction may be contributory. When impaction is a factor, it should be managed urgently.

Opioid rotation or a change in route of administration could be considered as a strategy to address chronic nausea. In two small studies, a switch from the oral to the subcutaneous route produced significantly less nausea and vomiting [99,100]. By contrast, there are conflicting data as to the benefit of switching from the oral to the rectal route [99,101-103]. Nevertheless, at least two systematic reviews [104,105] have concluded that there was some weak evidence for changing the opioid or the route of administration in patients with cancer who are experiencing persistent opioid-induced nausea and vomiting. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'Selecting the route of administration' and "Cancer pain management with opioids: Optimizing analgesia", section on 'Pain that respond poorly to opioids alone'.)

Chronic nausea usually responds to the same group of drug therapies that are used for acute nausea (table 5) [106,107]. The available evidence supports use of a dopamine antagonist, such as prochlorperazine or metoclopramide (also a prokinetic drug [104,108]), or a serotonin receptor antagonist, such as ondansetron [108-110], as usual first-line agents. However, the data are of very low quality, and the choice of antiemetic is either empirical, or based on the presumed underlying mechanism (eg, a prokinetic agent for patients with features of delayed gastric emptying, or an antihistamine antiemetic for a patients with enhanced vestibular sensitivity) [111].

Although both metoclopramide and prochlorperazine can cause extrapyramidal symptoms, metoclopramide has the advantage of causing less sedation and promoting gastric motility. On the other hand, 5-hydroxytryptamine type 3 (5HT3) receptor antagonists have the disadvantage of exacerbating constipation in patients who might already be experiencing opioid-induced gastrointestinal dysmotility. (See "Characteristics of antiemetic drugs".)

If a conventional dopamine antagonist is not tolerated, switching to an atypical antipsychotic agent, such as olanzapine or risperidone, also may be considered. A small observational retrospective study found that risperidone 1 mg daily orally [112] decreased refractory nausea and vomiting thought to be due to opioids in patients with advanced cancer. Furthermore, in the setting of chemotherapy-induced nausea and vomiting, olanzapine has been shown to reduce chronic nausea [113]. (See "Assessment and management of nausea and vomiting in palliative care", section on 'Medications including opioids'.)

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

Some patients who experience nausea with movement or nausea associated with vertigo may respond to an anticholinergic drug, such as scopolamine, or an antihistamine, such as meclizine [114].

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

Patients with epigastric pain or burning should be offered a trial of a proton pump inhibitor, such as pantoprazole, or a histamine 2 (H2) receptor antagonist, such as famotidine.

Myoclonus — Myoclonus (brief involuntary contractions of a muscle or group of muscles) may accompany acute encephalopathy of any cause and may occur in association with opioid-induced neurotoxicity. It is often associated with somnolence and mental clouding. The etiology may be multifactorial, with contributions from other drugs and/or metabolic disturbances.

The available evidence for treatment of myoclonus comes almost exclusively from published case reports. A systematic review concluded that the available data were insufficient to confirm or refute the benefits of any drug for the management of opioid-induced myoclonus [87].

If treatment is considered, the usual approach is to try a low dose of the benzodiazepine clonazepam (0.5 mg orally every six to eight hours [115]) or lorazepam (0.5 to 1 mg orally, sublingually, or intravenously every two to three hours). A trial of an anticonvulsant is rarely considered. A change to another opioid or the addition of an adjuvant analgesic may permit a reduction in opioid dose, relieving the myoclonus. (See "Cancer pain management: Role of adjuvant analgesics (coanalgesics)".)

Neuroendocrine effects — Opioids affect the functioning of the hypothalamic-pituitary-adrenal axis, resulting in increased levels of prolactin, decreased levels of sex hormones, and rarely, secondary adrenal insufficiency [116-118]. (See "Clinical manifestations of hypopituitarism".)

The potential for clinically significant opioid-induced hypogonadism is receiving increased attention [118]. (See "Causes of secondary hypogonadism in males" and "Clinical features and diagnosis of male hypogonadism" and "Evaluation and management of secondary amenorrhea" and "Pathogenesis and causes of spontaneous primary ovarian insufficiency (premature ovarian failure)".)

Hypogonadism may lead to troubling symptoms such as sexual dysfunction, fatigue, or depressed mood, or cause problems such as accelerated bone loss or infertility. If these symptoms or problems are occurring in opioid-treated patients, it is important to recognize the possibility of drug-related toxicity.

For males, there are conflicting reports as to the benefits of testosterone replacement therapy. While one review suggests that testosterone replacement therapy is safe and effective for opioid-induced hypogonadism [119], another reveals that the evidence of effectiveness is of very low to low quality and suggests only possible benefit for pain and emotional functioning but no benefit for sleep quality, depressed mood, or sexual or physical functioning [120]. On the other hand, new information is available from an analysis of 21,272 long-term male opioid users receiving treatment in the United States Veterans Health Administration (VHA) who had low free or total testosterone levels, of whom 14,121 received testosterone treatment and 7151 did not [121]. After adjusting for covariates (sociodemographic variables, physical and mental comorbidities, specific medications), long-term opioid users who received testosterone had significantly lower all-cause mortality (hazard ratio [HR] 0.51, 95% CI 0.42-0.61) and a lower incidence of major adverse cardiovascular events (HR 0.58, 95% CI 0.51-0.67), anemia (HR 0.73, 95% CI 0.68-0.79), and femoral or hip fractures (HR 0.68, 95% CI 0.48-0.96) than their counterparts who received opioids only.

These issues must be considered in context. In particular, their relevance in patients treated with opioids for pain related to active cancer or another advanced illness is unclear. However, many cancer patients report symptoms that could be related to hypogonadism, and these concerns may adversely impact quality of life. Given the recent data discussed above, which are reassuring in terms of risk and suggest potential benefits from testosterone replacement, clinicians should assess for these quality of life concerns in males and measure testosterone levels if there is no contraindication to testosterone treatment and the goals of care support an evaluation. If testosterone levels are low and the clinical setting is appropriate, a trial of testosterone treatment is reasonable. Testosterone treatment of male hypogonadism is discussed in more detail elsewhere. (See "Testosterone treatment of male hypogonadism".)

For females, the data are more limited. Nonetheless, it is reasonable to take a similar approach. Postmenopausal symptoms and symptoms of fatigue, depressed mood, and sexual dysfunction should be assessed if clinically appropriate. If there is no contraindication to estradiol treatment, blood levels of sex hormones should be measured, and a trial of estrogen therapy should be considered if levels are low. (See "Treatment of hypopituitarism", section on 'LH and FSH deficiency'.)

Sleep-disordered breathing — A syndrome of opioid-induced sleep-disordered breathing is becoming recognized as a risk during long-term opioid therapy. Opioid therapy may exacerbate an existing central or obstructive sleep apnea syndrome or may initiate obstructive sleep apnea in those predisposed by other factors, such as obesity or short neck. Opioid therapy can also be associated with the development of a central or mixed syndrome, even in those without known predisposing factors. Patients with symptoms that may indicated a sleep apnea syndrome, such as daytime somnolence, poor or nonrestorative sleep, significant fatigue or snoring, and patients who have significant risk factors for obstructive sleep apnea, such as obesity, should be treated cautiously with opioids. A concern about sleep-disordered breathing also should lead to very cautious use of cotreatment with centrally acting drugs that also may impact sleep, particularly the benzodiazepines. If the clinical setting is appropriate, the patient with sleep-related symptoms or daytime somnolence can undergo further evaluation.

The American Academy of Sleep Medicine (AASM) has released a position statement on chronic opioids and sleep, which highlights opioids as a risk factor for respiratory depression during sleep, sleep-disordered breathing, and altered sleep architecture [122]. In-laboratory polysomnography (PSG) is the test of choice to diagnose sleep-disordered breathing due to chronic opioids; supplemental use of carbon dioxide monitoring during PSG is required to detect sleep-related hypoventilation. Positive airway pressure therapy is suggested in symptomatic patients and those with moderate to severe sleep apnea on PSG. This subject is discussed in more detail elsewhere. (See "Sleep-disordered breathing in patients chronically using opioids".)

Respiratory depression — Respiratory depression is commonly considered a serious adverse effect of opioid drugs, but it is rarely a problem when therapy is administered according to accepted guidelines, particularly when dose titration is performed using relatively small increments (25 to 50 percent) and at intervals long enough to observe the effects of a dose at steady state drug concentrations [123-125]. Tolerance usually develops rapidly to this effect, allowing escalation of the dose without clinically significant respiratory effects. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'Dose titration'.)

Greater caution is needed when opioids are administered in the setting of cardiopulmonary disorders, a sleep apnea syndrome, or some other serious comorbidity that may limit ventilatory reserve, or when the opioid is combined with a sedative-hypnotic or a gabapentinoid:

Concurrent use of benzodiazepines in opioid-treated patients increases the risk of respiratory depression and other serious adverse events [126]. In 2016, the US Food and Drug Administration (FDA) issued a safety communication and now has a new boxed warning against the combined use of opioids and benzodiazepines or other central nervous system (CNS) depressants due to increased risk of respiratory depression and death. Despite this warning, the concurrent use of opioids with benzodiazepines or nonbenzodiazepine sedatives continues to be frequent, at least among patients with cancer [127].

Gabapentin and pregabalin enhance the CNS depressive effects of other centrally-acting drugs, including opioids, and there is an increased risk of oversedation, respiratory depression, or a serious adverse consequence (including death) when gabapentin or pregabalin is added to an opioid regimen [128,129]. Based on review of available pharmacovigilance data, in 2020, the FDA mandated revisions to the labeling regarding the risk of severe and life-threatening respiratory depression with use of gabapentinoids, particularly in combination with CNS depressants (eg, opioids), in those with underlying respiratory disease and in older adults [130].

Even in the latter setting, however, cautious selection of the initial dose and conservative incremental dose titration limit the risk of respiratory depression. (See 'Sleep-disordered breathing' above.)

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

Naloxone — Administration of the short-acting opioid antagonist naloxone can reverse opioid-induced respiratory depression. The US Food and Drug Administration now recommends that health care professionals discuss the availability of naloxone with all patients when prescribing opioid pain relievers, and to consider prescribing it to patients who are at increased risk for an opioid overdose (eg, concomitant use of benzodiazepines or other medicines that depress the CNS, patients who have a history of opioid use disorder, or patients who have experienced a previous opioid overdose) [131]. (See "Acute opioid intoxication in adults", section on 'Basic measures and antidotal therapy' and "Cancer pain management: General principles and risk management for patients receiving opioids", section on 'Preventing lethal overdose'.)

However:

It is essential to recognize that partial reversal of respiratory disturbances by naloxone in an opioid-treated patient does not mean that the opioid is the primary cause of the problem, particularly if respiratory problems developed during a period of relatively stable dosing. Regardless of a naloxone response, a search for a concurrent acute process (eg, pulmonary embolism, pneumonia), which may have combined with subclinical opioid effects, is often appropriate in the cancer population.

Naloxone should not be given to somnolent but easily arousable patients, unless there is significant slowing of the respiratory rate or the assessment suggests that the opioid effect may be rapidly evolving. If the opioid dose and the timing of the last several doses is known, the patient is past the peak concentration of the drug, and the severity of respiratory compromise is not severe, it is best not to treat with naloxone, but rather to withhold further opioid doses until the respiratory rate rises or pain returns.

Naloxone should be reserved for symptomatic respiratory depression, which is usually defined as obtundation combined with a respiratory rate of less than 8 breaths per minute. The risks of precipitating a withdrawal syndrome associated with the use of naloxone relatively contraindicate its use in other situations.

If naloxone is given due to concern about the severity of respiratory compromise, the treatment goal should be reversal of the respiratory effects and not a normal level of consciousness.

If needed, it is best to administer naloxone using small bolus injections of dilute solution (ie, by diluting a 0.4 mg [1 mL] ampule with 9 mL of normal saline for a total volume of 10 mL, thus creating a 0.04 mg/mL concentration), which should be titrated against respiratory rate. Repeated doses of 1 to 2 mL are often necessary every 45 minutes to an hour, as naloxone’s half-life is shorter than that of most opioids. Patients receiving sustained-release opioid formulations or long half-life drugs (eg, methadone or levorphanol) may require a naloxone infusion to prevent recurrence of respiratory depression.

Naloxone may be given nasally, subcutaneously (using a naloxone autoinjector "pen," which is sometimes dispensed to the patient who is receiving chronic opioids in case of an inadvertent overdose), or intramuscularly if there is a delay in securing intravenous access. When given by these routes, there is slower absorption and delayed elimination, making the drug much more difficult to titrate. (See "Prevention of lethal opioid overdose in the community".)

Pruritus — Pruritus is observed in 2 to 10 percent of patients receiving chronic opioids [132]. The mechanism is uncertain [133]. 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 with pruritus [107,134,135]. There is increasing evidence that opioid-induced pruritus is mediated through central mu-opioid receptors [136].

There are no prospective studies on the treatment of opioid-induced pruritus. Despite the controversy as to the role of histamine in opioid-induced pruritus, antihistamines are commonly used as first-line agents, with varying degrees of success [107,133]. Based upon anecdotal experience, some patients report improvement with daily administration of one of the nonsedating antihistamines, such as loratadine, cetirizine, or fexofenadine; there is no information about drug-selective effects within this group of agents. Some patients prefer using diphenhydramine two or three times per day. Anecdotal experience also suggests benefit from paroxetine [137], and gabapentin may be tried empirically. Another option is opioid rotation [138].

Low doses of opioid antagonists (eg, nalmefene 10 to 25 mcg intravenously, nalbuphine 1 to 5 mg intravenously/intramuscularly) are effective for treatment of pruritus in patients with non-cancer pain receiving short-term opioids in the postoperative setting, without reversal of opioid analgesia [133,139,140]. However, long-term use of opioid antagonists in patients with cancer pain who are experiencing prolonged opioid-induced pruritus has not been investigated [139].

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

Urinary retention — Opioids can cause urinary retention. This effect, which is more common in males, may be due to a combination of reduced bladder tone and increased contraction in the urinary bladder sphincter [141-143]. Although coadministration of a nonopioid analgesic therapy that has opioid-sparing effects could presumably reduce the risk of dose-dependent side effects, concomitant nonsteroidal anti-inflammatory drug (NSAID) therapy has not been shown to impact positively on the risk of urinary retention

If acute urinary retention occurs, catheterization of the bladder may be necessary. The dose of the opioid should be lowered and an effort should be made to reduce or eliminate drugs that may be contributing, such as drugs with anticholinergic effects.

Opioid antagonists, including low-dose naloxone, are effective in reversing urinary retention in the context of acute pain management, but they also may reverse analgesia [144]. Peripherally acting mu-opioid receptor antagonists (PAMORAs) such as methylnaltrexone and mixed agonist-antagonist drugs such as nalbuphine may be effective [145-147], but the evidence of benefit from these classes is very limited. Anecdotally, some patients appear to respond to drugs used to treat urinary retention related to prostatic hypertrophy, such as the alpha-1 blockers doxazosin or tamsulosin. (See "Medical treatment of benign prostatic hyperplasia", section on 'Alpha-adrenergic receptor blockers for most patients'.)

Infection risk — Preclinical studies have found that some opioids (especially morphine, methadone, and fentanyl) have immunosuppressive properties, including reduced natural killer cell cytotoxicity and impairment of neutrophil chemotaxis [148-151]. The relationship between opioid use and infection risk in humans has been examined in four epidemiologic studies, all of which suggest that prescription opioids are associated with an increased risk of serious infection [152-155]. As examples:

In a case-control study in which immunocompetent adults aged 65 to 94 with community-acquired pneumonia, as identified through health plan records, were compared with matched controls (for age, sex, and calendar year), current opioid use was associated with a 38 percent greater risk for community-acquired pneumonia compared with nonuse (odds ratio [OR] 1.38, 95% CI 1.08-1.76) [152]. Risk was highest for opioids characterized as immunosuppressive based upon preclinical studies (ie, morphine but not hydromorphone or oxycodone) and for use of long-acting opioids (OR 3.43, 95% CI 1.44-8.21) but not short-acting opioids (OR 1.27, 95% CI 0.98-1.64).

Additional evidence for an association between opioids and infection comes from a case-control study conducted in a Tennessee Medicaid population [154]. The 1233 case patients with laboratory-confirmed pneumococcal disease (pneumonia or another infection with isolation of Streptococcus pneumoniae from a normally sterile site, such as the blood or cerebrospinal fluid) aged five and older were matched with 24,300 control participants by diagnosis date, age, and county of residence. Opioid use was measured based on pharmacy prescription records. Results were adjusted for many potential confounders, including markers of frailty. Individuals with invasive pneumococcal disease had greater odds than controls of being current opioid users (adjusted odds ratio [aOR] 1.62, 95% CI 1.36-1.92). Associations were strongest for long-acting opioids (aOR 1.87, 95% CI 1.24-2.82), high-potency opioids (morphine, codeine, oxycodone, hydromorphone, fentanyl), and higher opioid doses (especially ≥90 morphine milligram equivalents per day).

In a separate analysis using the same population of Tennessee Medicaid enrollees 18 years of age or older who were initiating long-acting opioids, hospitalization rates for serious infection were compared among 22,811 opioid users who received oxycodone, oxymorphone, or tramadol and 61,240 patients who received morphine, methadone, or fentanyl [155]. The former group had a significantly lower infection rate (adjusted incidence rate ratio [aIRR] 0.78, 95% CI 0.66-0.91), and in a comparison across opioids, oxycodone users had a lower rate of infection than did morphine users (aIRR 0.73, 95% CI 0.60-0.89).

Taken together, these studies support the view that certain opioids may increase the risk of some serious infections, an outcome that appears consistent with preclinical studies that demonstrate the potential for opioid-related immunosuppressive effects. Additional studies are needed to confirm these observations and determine whether risk varies with specific patient characteristics or different types of pathogens. At present, it is reasonable for clinicians to consider an increased risk of serious infection as a potential adverse opioid effect. Based on the information available, this risk may be relatively higher with morphine, methadone, and fentanyl, but additional studies will be needed to clarify the clinical implications of these data.

Weight gain and abnormal glycemic control — Studies of patients receiving methadone therapy for addiction have noted an association between this opioid and weight gain [156-164]. Opioid therapy in both this population and those treated for pain can lead to abnormal glycemic control; both hyperglycemia and hypoglycemia have been observed [165]. For patients with opioid addiction, loss of glycemic control may be related, in part, to a heightened taste preference for sweet foods, a slowing of gastric motility, delayed absorption of glucose, and a delayed insulin response [156,166,167]. Further studies are needed to characterize this potential for opioid-induced change in glycemic control and to determine the extent to which it is clinically relevant in patients with pain, many of whom have prediabetic conditions or frank diabetes. Given the limitations in the extant data, there are presently no specific guidelines related to this potential risk.

Opioid-induced hyperalgesia — In the laboratory, opioid-induced hyperalgesia (OIH) is a well-established, easily reproducible state characterized by an exaggerated response to noxious stimuli or the occurrence of nociceptive responses to non-noxious stimuli. This state can be produced by exposure to opioids and preclinical studies have investigated the factors that can modulate OIH development, as well as the underlying cellular and molecular mechanisms [168-171].

Whether or not OIH is a clinically relevant phenomenon continues to be debated. Although studies in those with addiction and in human volunteers that demonstrate different nociceptive profiles than those in opioid-naïve patients suggest that the phenomenon occurs in humans and may contribute to the overall response to opioid therapy, this conclusion has been questioned based on the populations studied and the methodologies employed [172-174].

If OIH occurs, it would be characterized by a paradoxical response, whereby a patient receiving opioids for the treatment of pain may actually become more sensitive to certain painful stimuli and, in some cases, experience pain from ordinarily non-painful stimuli (allodynia) [175]. Although solid evidence for the existence of OIH in patients with chronic non-cancer or cancer-related pain is lacking [176], clinical observations suggest that it may be important, at least in some patients or some clinical settings [168,169,174,177]. A systematic review of the evidence for OIH in humans concluded that OIH was evident in patients after chronic opioid exposure, but that the findings were dependent on both the pain stimulus and assessment measures [177]. Anecdotal experience suggests that rare patients receiving escalating doses of an opioid may develop increasing pain and sensitivity of the skin in association with mental clouding and myoclonus; in the absence of other causes, this presentation suggests OIH, particularly if an improvement in pain follows opioid dose reduction. Cases such as this support the view that the experimental phenomenon of OIH may have a clinical correlate, which manifests rarely.

When individual patients 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 and, possibly, confusion during a period of aggressive opioid escalation, an element of OIH may be occurring. Diagnosis may be complicated if this occurs in association with delirium and the patient is observed to become seemingly more distressed by pain as extra boluses of opioids are given. The diagnosis of OIH (and possibly delirium) should be considered in all patients with worsening or more-diffuse pain during a period of aggressive opioid escalation.

There is no well-established treatment for OIH [178]. When suspected, it is reasonable to consider opioid rotation [179] or the use of a nonopioid strategy for pain control.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Constipation" and "Society guideline links: Palliative care" and "Society guideline links: Cancer pain".)

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 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics 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.)

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

SUMMARY AND RECOMMENDATIONS

Opioid-induced constipation – The most common and persistent side effect from chronic opioid use is opioid-induced constipation (OIC). (See 'Opioid bowel dysfunction' above.)

Diagnosis is based on clinical history, physical examination (including rectal examination when appropriate), and limited diagnostic studies, as clinically indicated. Diagnostic criteria are available (the Rome-IV criteria). (See 'Diagnosis' above.)

We suggest prophylactic therapy for all patients at the time of opioid initiation (Grade 2C). We use daily administration of a contact cathartic such as senna, with or without a stool softener, or an osmotic laxative (table 2). (See 'Prevention' above.)

For patients who develop OIC despite prophylaxis, we suggest additional treatment with conventional laxatives rather than immediately starting a prescription drug (Grade 2C). For most patients, we switch to a different laxative than was used for prophylaxis, with dose escalation as tolerated (table 1). We avoid lactulose in lactose-intolerant patients, and restrict use of a stool softener to patients with hard, dry stools. (See 'Initial management' above.)

Patients who have passed no stool in several days and who have no evidence of bowel obstruction or ileus may require manual disimpaction. Once an impaction has been ruled out or cleared, laxative therapy may be started.

Increased consumption of fluids and soluble dietary fiber and increased physical activity may help some patients (table 1). Fiber should not be increased if the patient is debilitated, bowel obstruction is suspected, or hydration cannot be maintained. (See 'Initial management' above.)

Regular ingestion of probiotics can improve chronic constipation; a trial in patients with OIC is reasonable. (See 'Other therapies' above.)

For patients with refractory OIC who do not have a bowel obstruction, we suggest a trial of a PAMORA (Grade 2B). The choice of agent is empiric, but experience is greatest with subcutaneous methylnaltrexone. (See 'Management of refractory opioid-induced constipation' above.)

If an oral agent is preferred, options include naloxegol, oral methylnaltrexone, or naldemedine. Another alternative is linaclotide. (See 'Other therapies' above.)

Clinicians should use caution when administering PAMORAS to patients with known or suspected lesions in the intestinal wall, given the rare serious side effects observed with methylnaltrexone, and should stop the drug immediately for worsening of gastrointestinal symptoms. (See 'Methylnaltrexone' above.)

Sedation and mental clouding – Opioid therapy can cause somnolence or mental clouding, which typically wanes over a period of days or weeks but may persist. A stepwise treatment approach includes (see 'Somnolence and mental clouding' above):

Assess and treat for contributing causes, if consistent with the goals of care. Reduce or eliminate concomitant use of centrally acting medications, especially central nervous system depressants.

If analgesia is satisfactory, an empiric trial of opioid dose reduction is a reasonable first step. If analgesia is unsatisfactory, options include opioid rotation, or administration of a coanalgesic to achieve an opioid-sparing effect. Another option is an empiric trial of a psychostimulant such as methylphenidate or modafinil. (See 'Psychostimulants' above.)

Other side effects

Nausea frequently complicates opioid initiation, but it is infrequently persistent. Options include a lower opioid dose, opioid rotation, or a change in the route of administration. Patients who do not respond to these approaches should be evaluated for other etiologies and the condition, if identified, should be treated. Otherwise, we treat empirically with an antiemetic (table 5). (See 'Nausea and vomiting' above.)

Therapeutic options for myoclonus include clonazepam 0.5 mg orally every six to eight hours, lorazepam 0.5 to 1 mg orally, sublingually, or IV every two to three hours, an anticonvulsant, or opioid rotation. (See 'Myoclonus' above.)

Patients with symptomatic hypogonadism should be assessed for the risks and potential benefits of hormone replacement therapy. (See 'Neuroendocrine effects' above.)

Opioids can worsen preexisting sleep apnea syndrome, precipitate obstructive sleep apnea in predisposed patients, or cause central or mixed sleep apnea. Patients with suspected sleep-related symptoms or daytime somnolence should undergo further evaluation with polysomnography (PSG). (See 'Sleep-disordered breathing' above.)

Respiratory depression is rarely a problem when opioids are administered according to accepted guidelines. Clinicians should discuss with patients and caregivers whether it would be appropriate to coprescribe a naloxone "pen" or inhaler to have at home on an as needed basis. (See 'Respiratory depression' above.)

Opioid-induced pruritus is uncommon but distressing. Therapeutic options include antihistamines, paroxetine, or opioid rotation. (See 'Pruritus' above.)

Opioid-induced hyperalgesia should be considered when worsening pain and tremulousness, often with cognitive impairment, is occurring with opioid dose escalation. Therapeutic options include opioid rotation or a switch to a nonopioid analgesic. (See 'Opioid-induced hyperalgesia' above.)

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Topic 2800 Version 73.0

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