Secondary Logo

Journal Logo

Opioid-induced Hallucinations: A Review of the Literature, Pathophysiology, Diagnosis, and Treatment

Sivanesan, Eellan MD; Gitlin, Melvin C. MD, FACPM; Candiotti, Keith A. MD

doi: 10.1213/ANE.0000000000001417
Ambulatory Anesthesiology
Continuing Medical Education

Despite their association with multiple adverse effects, opioid prescription continues to increase. Opioid-induced hallucination is an uncommon yet significant adverse effect of opioid treatment. The practitioner may encounter patient reluctance to volunteer the occurrence of this phenomenon because of fears of being judged mentally unsound. The majority of the literature concerning opioid-induced hallucinations arises from treatment during end-of-life care and cancer pain. Because the rate of opioid prescriptions continues to increase in the population, the rate of opioid-associated hallucinations may also conceivably increase. With a forecasted increase in the patient-to-physician ratio, opioid therapy is predicted to be provided by practitioners of varying backgrounds and medical specialties. Hence, knowledge of the pharmacology and potential adverse effects of these agents is required. This review seeks to increase awareness of this potential complication through a discussion of the literature, potential mechanisms of action, diagnosis, and treatment strategies.

Published ahead of print June 1, 2016.

From the Department of Anesthesiology, Perioperative Medicine, and Pain Management, University of Miami Miller School of Medicine, Miami, Florida.

Published ahead of print June 1, 2016.

Accepted for publication April 11, 2016.

Funding: None.

The authors declare no conflicts of interest.

This report was previously presented, in part, at the 2015 Annual Meeting of the American Society of Regional Anesthesia and Pain Medicine, Las Vegas, NV, May 14–16, 2015.

Reprints will not be available from the authors.

Address correspondence to Melvin C. Gitlin, MD, FACPM, Department of Anesthesiology, Perioperative Medicine, and Pain Management, University of Miami Miller School of Medicine, Central 300, JMH, 1611 NW 12th Ave, Miami, FL 33136. Address e-mail to

Opioid prescription for both chronic cancer and noncancer pain has been steadily increasing over the past few decades.1,2 Although the use of opioid therapy for noncancer pain remains controversial, it is utilized in the treatment for a multitude of conditions. With a forecasted increase in the patient-to-physician ratio, opioid therapy is predicted to be provided by practitioners of varying backgrounds and medical specialties. Hence, knowledge of the pharmacology and potential adverse effects of these drugs is required. Treatment of pain conditions is at the forefront of public debate. The economic loss of pain conditions to the United States in 2007 was estimated to be a total of $55.7 billion with workplace costs accounting for $25.6 billion (46%) and health care costs accounting for $25.0 billion (45%).3

Opioid therapy may be associated with adverse effects. At the extreme, 16,235 of 22,235 (71.3%) pharmaceutical overdose deaths in 2013 involved opioid analgesics.4 The most common adverse effects are gastrointestinal and central nervous system-related. Up to 80% of patients treated with opioids experience a minimum of 1 adverse event.5,6 Common adverse events noted across multiple studies include xerostomia (42%), constipation (20%–41%), diaphoresis (34%), weight gain (29%), somnolence (14%–29%), sleep disorders (25%), memory deficits (24%), decreased appetite (23%), nausea (17%–33%), concentration deficits (19%), fatigue (19%), sexual dysfunction (18%), dizziness (12%–22%), emesis (11%–15%), pruritus/dry skin (10%), and urinary retention (4%–18%).5–14 Other adverse effects whose incidences are more difficult to quantify include hyperalgesia, muscle rigidity, myoclonus, immunologic and hormonal dysfunction, physical dependence, tolerance, and addiction.10

Opioid-induced hallucination is an uncommon yet significant adverse effect of opioid treatment, frequently attributed to underlying psychiatric disease or personality disorder rather than a direct neurobiologic effect of opioids. This phenomenon is likely underreported because of the tolerable intensity of many hallucinations and fear associated with the stigma of being labeled as psychologically unstable.15 This review seeks to increase awareness of this potential complication through a discussion of the literature, potential mechanisms of action, diagnosis, and treatment strategies.

Back to Top | Article Outline


A search was conducted using MEDLINE/PubMed, MeSH, Cochrane Review, and Google Scholar. The search words included “opioid” and “hallucinations” combined with “neurotoxic,” “delirium,” “neuroexcitatory,” “adverse effects,” “hallucinosis,” “fentanyl,” “morphine,” “pentazocine,” “hydromorphone,” “oxycodone,” “naloxone,” “methadone,” “tramadol,” “remifentanil,” “sufentanil,” “alfentanil,” “buprenorphine,” or “meperidine.” No language restrictions or date limits were applied. Although a sweeping number of case reports were identified, the paucity of prospective studies, despite the broad search criteria applied, limits the definition of conclusive recommendations regarding diagnostic and treatment options. Articles were included if they related hallucinations to opioid treatments. The reference lists of the articles selected for review were also scrutinized to identify the additional studies not found using the original search terms.

Back to Top | Article Outline


One thousand two hundred fifty-three articles were identified after the database search using the aforementioned methods. After a manual review of their abstracts, most articles were rejected because they did not identify hallucinations with concurrent opioid administration. Fifty-six articles met search criteria for hallucination development linked to opioid treatment.

Back to Top | Article Outline

Review of the Literature

The word “hallucination” has its origin in the Latin root hallucinari or allucinari, which translates to “wander in mind.”16 The following is the Diagnostic and Statistical Manual of Mental Disorders’ definition of a hallucination: “a perception like experience with the clarity and impact of a true perception but without the external stimulation of the relevant sensory organ.”17

Numerous reports exist of hallucinations attributed to opioids, which have been typically described as auditory, visual, or rarely tactile hallucinations.18 The majority of the literature arises from treatment during end-of-life care and cancer pain. Many of these reports involve high-dose opioid regimens, both planned and accidental. They are often reported in patients with comorbidities that may predispose to hallucinations, yet they are also seen in patients without any underlying confounders. Most reports have cited morphine as the causative agent, but there is also a multitude of reports implicating fentanyl, methadone, tramadol, hydromorphone, buprenorphine, pentazocine, and oxycodone.18–26 Conversely, there have been reports of opioid-induced hallucinations, which are reversed by rotation to oxycodone.27,28

The first reports of opioid-induced hallucinations in the literature were associated with the use of pentazocine, a mixed agonist/antagonist opioid belonging to the synthetic benzomorphan class.29,30 A report of 57 cases linked to acute pentazocine overdose collected over 10 years included 3 patients with neuroexcitatory symptoms, 2 of whom reported visual hallucinations, delusions, and paranoid ideation.30 Earlier studies had attributed these symptoms to the agonist action of pentazocine on sigma opioid receptors.29,31 Pentazocine-associated hallucinations are now reported much less frequently reflective of its diminished use in favor of other opioids.

Morphine remains the opioid most commonly associated with opioid-induced hallucinations. This may be attributed to its long history of use and widespread availability. The association between morphine and hallucinations was reported on multiple occasions in The Lancet several decades ago.27,32,33 A study conducted over 14 months by Caraceni et al34 involving 161 patients with cancer-related chronic pain who were administered opioids for at least 1 week reported that 9 of these patients developed hallucinations with morphine administration, 8 of which were categorized as primarily visual. The accumulation of morphine metabolites, particularly morphine-3-glucoronide, has been linked to the development of neurologic phenomena.35 Morphine has also been linked to the development of musical (auditory) hallucinations, although this occurs less frequently than visual symptoms.36

Bruera et al26 reported 4 cases of patients developing organic hallucinosis of a total 55 patients receiving chronic opioids for cancer pain. He defined the term organic hallucinosis to describe the development of hallucinations in individuals without pre-existing cognitive impairment. All 4 of these patients were receiving hydromorphone and described their hallucinations as visual. These hallucinations subsequently resolved with opioid rotation to diamorphine or morphine and concomitant administration of haloperidol.26

A single report appears to be the first describing oxycodone-induced musical hallucinations.24 There is also a single report of oxycodone-induced visual hallucinations in the context of serotonin syndrome associated with that opioid and acute dose escalation.23 Notably, most of the literature involving oxycodone and hallucinations involves its use in opioid rotation as a treatment for opioid-induced hallucinations.27,28

Hallucinations with fentanyl use have been reported to occur at a rate as high as 6% (5 of 82 patients) during its use in patient-controlled intravenous analgesia for postoperative acute pain management.37 Case reports link fentanyl and hallucinations with the high doses used in the context of cancer pain management.19,38,39 A patient with gastric adenocarcinoma described the development of visual hallucinations after accidental administration of 5000 μg fentanyl instead of a scheduled 100-μg dose.38 Because the hallucinations ceased immediately after administration of 0.1 mg naloxone, it was postulated that these were caused by fentanyl and that opioid toxicity may result in neuroexcitation as opposed to its more traditionally noted depressant effects.38 Fentanyl-induced hallucinations have been reported within a few days of initiation when this drug has been administered through a transdermal patch.19,39 This increased incidence was hypothesized to occur because of the variability in transdermal absorption, which can lead to increased peak plasma concentrations.19 Norfentanyl, a metabolite of fentanyl, has been noted to share structural similarities with normeperidine and may cause neuroexcitation through a similar mechanism as that known to occur with normeperidine accumulation.39

The frequency of hallucinations with methadone use appears to be rare with 1 retrospective review finding an incidence of 4 in 3000 patients on a chronic methadone maintenance program.40 There also exist only 2 case reports associating methadone with hallucinations with 1 seen in the pediatric literature and the other noted in the management of an adult with gastric carcinoma.20,33 Although morphine metabolism relies on glucuronidation, methadone is metabolized by the type I cytochrome P450 group of enzymes. Thus, toxicity may be related to polypharmacy affecting these same enzymes.41 The mechanism of methadone-induced hallucinations may also differ because, in addition to its affinity for opioid receptors, it is also an N-methyl-d-aspartate antagonist and inhibitor of monoamine reuptake.

A study using the French Pharmacovigilance Database, which recorded 469,181 reports of adverse effects between 1985 and 2013, found that 482 patients reported hallucinations of the total 12,184 patients who had received opioids.42 Although the duration of opioid therapy was not standardized, these data provide suggestion to the overall incidence of opioid-induced hallucinations.42 Tramadol was involved most often with an incidence of 240, an odds ratio of 6.3, and 95% confidence interval of 5.5 to 7.2, whereas morphine was next with an incidence of 143, an odds ratio of 4.4, and 95% confidence interval of 3.7 to 5.2. The increased incidence associated with tramadol may occur because along with its opioid-agonist properties, it also inhibits reuptake of norepinephrine and serotonin. In an earlier report of 2 cases, hallucinations occurring 6 days after flu immunization and chronic tramadol administration were hypothesized to occur through antigen-specific production of interferon-γ by lymphocytes that interfered with CYP3A4 activity and expression.43 Musical hallucinations have also been reported shortly after starting tramadol when it was used as a part of a palliative treatment regimen.21

This review did not reveal any reports that attribute hallucinations to the use of remifentanil, sufentanil, or alfentanil. Plausible explanations for this lack of association include their preferential agonism of the κ and δ opioid receptors, often short duration of treatment, short elimination half-lives, and the frequent concurrent use of other sedatives and hypnotics, which may mask hallucinations.

Buprenorphine is frequently chosen as a therapeutic agent because of its low side effect profile and the ceiling on its depressant action because it functions as a mixed opioid agonist/antagonist. Initial case reports described the development of visual hallucinations within 2 days after epidural administration of buprenorphine after spine surgery in a series of 5 patients.44 Another case report described near fatal auditory hallucinations because of suicidal ideation after receiving a single dose of sublingual buprenorphine.45 Subsequent case reports have additionally reported tactile, visual, and auditory hallucinations with chronic intravenous administration.46,47 Neurotoxicity appears to be related to the accumulation of buprenorphine metabolites, N- desalkyl buprenorphine and buprenorphine-3-O-glucuronide.47 Another study linked hallucinations to a more direct excitatory or disinhibiting effect than other opioids on the limbic and extrapyramidal systems.44

Normeperidine, an active meperidine metabolite, has significant effects, which include confusion, anxiety, nervousness, seizures, and hallucinations.48 A retrospective study examining 355 records identified a 2% incidence of neurotoxicity after approximately 2 days of treatment, which directly correlated with plasma normeperidine levels.49 Meperidine is primarily metabolized through N-demethylation by the hepatic cytochrome P450 system to produce normeperidine.50 Subsequently, elimination of normeperidine occurs by both the liver and the kidneys.51 Normeperidine accumulation can occur as a result of enzyme-inducing drugs, hepatic failure, or renal failure.50–52 Some authors have suggested that the anticholinergic properties of meperidine and normeperidine are causative for hallucinations, because concomitant administration of cimetidine exacerbates neurotoxicity, whereas physostigmine is alleviating.53

Back to Top | Article Outline


Many hypotheses have been advanced to explain the etiology of opioid-induced hallucinations. One common feature of these hypotheses involves opioid-induced dopamine dysregulation.54–58 There is neuropsychiatric literature similarly associating schizophrenia with dopamine dysregulation. In particular, the mesolimbic dopaminergic system has been implicated in many of the central side effects.56 Along with hallucinations, other central adverse reactions include drowsiness, confusion, and nightmares.59 This system projects from the ventral tegmental area (VTA) to the nucleus accumbens (NAc).58 An overactivation of the dopaminergic pathways is thought to result in auditory and visual hallucinations. Opioid metabolites may have similar activity to the parent compound and, thus, enhance toxicity with accumulation.60 It is also possible that metabolites act through alternate receptors with alternate effects, as noted in the example of morphine metabolites having differential affinity for μ receptor subtypes and nonopiate receptors.61 Differing mechanisms of action may make some metabolites more likely to produce hallucinations than their parent compounds.

A previous study involving Sprague-Dawley rats demonstrated a positive dose-related correlation between opioids, specifically heroin, and dopamine concentration in the NAc.58 Conflicting reports have noted that opioid agonists potentiate this pathway, whereas others have found that agonist activity decreases dopamine release.56 However, the reported site of action differs, because κ-opioid agonist action at the NAc decreases dopamine release, whereas μ-opioid agonist action at the VTA increases dopamine release from the NAc.35,62 The release of dopamine by μ-receptor agonists has been postulated to occur through an indirect mechanism that involves hyperpolarization and subsequent inhibition of interneurons that normally provide γ-aminobutyric acid-mediated synaptic input to the dopamine cells.57,63 Thus, opioids potentiate disinhibition of dopamine cells.57 A previous study similarly demonstrated that μ-receptor binding in the VTA was not altered by destruction of dopamine-containing cells.64

There is no definitive answer as to whether metabolites or the parent compounds are more likely to produce hallucinations, and this may vary with the properties of each particular opioid. Although some metabolites act through different receptors than their parent compound, others exhibit similar agonist properties at the same receptors.61 Examples of well-studied metabolites exhibiting neurotoxicity include morphine-3-glucoronide, normeperidine, and hydromorphone-3-glucoronide.35,49,61 It remains to be determined whether the agonism of a particular subset of opioid receptors is more likely to prompt the development of hallucinations.

The dopamine neurons of the midbrain, including the VTA, have been linked to activity in the prefrontal cortex with a possible role for cognitive prefrontal cortex inhibition of dopamine release in the NAc.65–67 The NAc also receives ascending sensory input through multiple pathways including the hippocampus, amygdala, and hypothalamus.66 A phasic dopamine system has been linked to reward-based learning and the assignment of salience to sensory stimuli.68 Thus, it has been surmised that prefrontal cognitive function can alter salience to sensory stimuli by inhibiting dopamine release in the NAc. The altered salience of sensory stimuli can contribute to the development of hallucinations whereby internal representations are perceived as reality.66,69 These pathways, producing opioid-induced hallucinations, have been similarly associated with hallucinations because of cannabinoids, salvinorin A, schizophrenia, and dopamine agonists for Parkinson disease.57,70–72

Back to Top | Article Outline


To make a diagnosis of opioid-induced hallucinations, it is first necessary to rule out other possible etiologies. These include psychiatric disease, substance abuse, metabolic derangements, electrolyte disorders, infection, brain neoplasm, neurologic disease, ophthalmologic disease, inner or middle ear disease, toxins, vascular insult, endocrinopathies, and substance or psychiatric medication withdrawal.73–75 A thorough history and clinical examination can help differentiate opioid-induced hallucinations from other etiologies. Standard laboratory analysis may eliminate the most common electrolyte disorders and impaired metabolism because of hepatic or renal insufficiency. Impaired metabolism because of altered cytochrome P450 enzyme function may be suspected clinically with the examination of concurrently administered medications, although genetic variation can also account for differences in function.76,77 Numerous other genetic variations outside of the scope of this article can also alter opioid metabolism or action.59,78 Emergency situations may involve cerebrovascular accidents, neuroinfectious processes including meningitis and encephalitis, or suicidal ideations.79,80 These conditions require immediate evaluation and treatment.

The duration of hallucinations appears to be highly variable and, without treatment, it is likely to depend on the elimination properties of each particular opioid. Situations in which metabolism or excretion of either the parent compound or neurotoxic metabolites is impaired may lengthen the period of neurotoxic symptoms.81 Hallucinations are likely to be continuous until serum concentrations decrease; however, intermittent hallucinations have been observed with repeat opioid dosing after hallucination abatement or with the use of short-duration opioid antagonists.34,38

A challenging circumstance involves concomitant neuropsychiatric disease. The prevalence of hallucinations in Parkinson disease has been reported to be as high as 39.8% when all types of hallucinations are included.15 Initiation or dose escalation of dopamine agonists used in the treatment of Parkinson disease is particularly notable for its association with hallucinations.82,83 In schizophrenia, auditory hallucinations are most common with a prevalence of 74.8% followed by visual hallucinations (39.1%), cenesthetic hallucinations (28.9%), and tactile, olfactory, and gustatory hallucinations (1.3%–6.6%).84 Hallucinations have also been noted to occur with numerous other psychiatric illnesses. Despite these numbers, a patient with pre-existing psychiatric disease can develop hallucinations primarily attributable to opioids; furthermore, this population can be particularly susceptible. This may especially be the case in patients whose psychiatric disease had been stable before opioid dosing. It is not uncommon for a diagnosis of opioid-induced hallucinations to be discarded in favor of an exacerbation of a psychiatric disease resulting in the subsequent adjustment of psychotropic medications. In addition, cessation of antipsychotics or alteration of psychiatric medications should be suspected if the timing coincides with the development of hallucinations.

Although there are factors that increase the likelihood of this diagnosis, treatment is often based on clinical judgment rather than any specific test result. Similar clinical discretion is seen in the diagnosis of numerous other conditions such as in the treatment of anaphylaxis before receiving confirmatory serum tryptase levels.85 Exclusion of the aforementioned differential diagnoses, recent opioid administration, rapid opioid dose escalation, or eradication of hallucinations with opioid antagonists are all criteria that support the diagnosis of opioid-induced hallucinations.

Back to Top | Article Outline


If a diagnosis of opioid-induced hallucinations is made, there are a number of potential treatment options that may be considered. The simplest perhaps is to consider discontinuing opioid therapy if practical. However, this solution may not be possible in many situations. Opioid rotation or dose reduction can serve as an alternative to complete discontinuation. High-dose opioids administered intentionally or unintentionally have been reported to more likely result in neurotoxic effects including hallucinations.18,86,87 A dose reduction of 10% to 50% or increase in the frequency of administration for the same total dose has been applied previously to treat opioid neurotoxic effects.86–88 The addition of adjuvant pain medications utilizing a multimodal approach may help facilitate decreased opioid dosing. Efforts to reduce the likelihood of developing hallucinations may be made by conservative initial dosing and slow titration to achieve analgesia; nevertheless, clinical discretion with patient suffering under consideration may prompt a hastened speed of titration.

Opioid rotation has been utilized to help with suboptimal analgesia or adverse effects associated with the use of a particular opioid.89 There also exists weak evidence that changes in administration route can ameliorate side effects as seen with the reports of using parenteral or rectal routes instead of oral.86,88,90 The mechanism has been attributed to varying bioavailability or metabolism.90 Decreased dosing through epidural and intrathecal administration may also decrease the potential for accumulation of neurotoxic metabolites.88,91

The particular opioid suspected of inducing toxicity may also be switched to another opioid. A retrospective chart review reported that 81% of patients were able to obtain an effective balance of analgesia and side effects when up to 5 trials of substitution were consecutively performed with different opioids until successful.92 Rotation of an opioid from another class was previously suggested in a case where fentanyl, a piperidine derivative, was rotated out for hydrocodone, a phenanthrene derivative, with the successful elimination of the hallucinations.19 This same report further suggested the use of an NMDA antagonist such as ketamine to treat fentanyl-induced hallucinations.19 Nevertheless, this may not be advisable because ketamine is a known hallucinogen.93 Reduction or elimination of hallucinations through opioid substitution has been attributed to genetic variations in response to specific opioids among patients, clearance of the original opioid and its metabolites, or essentially decreased dosing of the new opioid because of incomplete cross-tolerance.88,94,95

Opioid antagonists are well known to reverse many opioid-associated adverse reactions.96 There are reports describing the successful use of naloxone and κ selective opioid antagonists in the treatment of hallucinations associated with schizophrenia.97–99 Naloxone is the most studied antagonist available for the treatment of schizophrenic hallucinations with a wide range of reported initial intravenous doses from 0.4 to 10 mg.98 Although this study noted increasing efficacy with higher dosing, caution is mandated because their use may be associated with adverse effects including acute withdrawal symptoms in chronic opioid users, pulmonary edema, seizures, arrhythmias, and hypertension.98,100 Furthermore, precipitated opioid withdrawal has been noted to cause hallucinations.101 The duration of action of the antagonists must be considered to avoid recurrence of hallucinations if these agents are deemed to be clinically indicated. Based on the elimination half-life of a particular opioid, a continuous antagonist infusion may be necessary as noted in the case of fentanyl-induced hallucinations, which were successfully treated with repeated intravenous dosing of 0.1 to 0.2 mg/h of naloxone followed by an infusion of 0.2 mg/h for 7 hours.38

Symptomatic management of hallucinations is an option that may include the use of antipsychotics, acetylcholinesterase inhibitors, and benzodiazepines.26,86,102–104 These treatments do not directly address the root cause of the hallucination but rather have been used in situations of urgency or refractory symptoms. Acetylcholinesterase inhibitors have been administered for the treatment of hallucinations of various etiologies such as schizophrenia and Parkinson disease.102–104 These studies report a similar hallucinatory mechanism among these disease processes involving anticholinergic activity. It has been hypothesized that opioids also exert multiple inhibitory effects on cerebral cholinergic activity.105,106 The successful use of physostigmine in the treatment of opioid-induced neurotoxicity, including hallucinations, has been reported as well.105

Antipsychotics, also known as neuroleptics, function as dopamine antagonists, whereas those classified as atypical antipsychotics also antagonize serotonin receptors. It is this dopamine antagonism, which is posited to alleviate hallucinations, because of limbic and frontal lobe dopamine release induced by opioids.106 Atypical antipsychotics may be preferred because they are less associated with extrapyramidal side effects. Interestingly, risperidone has been associated with antagonism of opioid action, even precipitating withdrawal, although the exact mechanism is unclear.107,108 Antipsychotics have commonly been used for the treatment of hallucinations because of numerous disease processes including schizophrenia, iatrogenic dopaminergic neurotoxicity, Bonnet syndrome, and Parkinson disease.109–113 Haloperidol has been noted to rapidly resolve opioid-induced hallucinations and accordingly it has been widely used.26

Psychostimulants such as methylphenidate, dextromethorphan, pemoline, and modafinil have been successfully used to treat many of the neurodepressant adverse effects associated with opioids.114–116 However, their use in treating opioid-induced hallucinations is not recommended because this stimulatory drug class can exacerbate neuroexcitatory effects including hallucinations.60 If these medications are taken concurrently with the development of suspected opioid-induced hallucinations, dose reduction or discontinuation may be considered.

Benzodiazepines may be considered if the hallucinations are refractory to dose reduction or rotation and harm to the patient or others is predicted. The ability of these agents to decrease agitation and anxiety may be desirable. This drug class has been noted to be particularly effective in treating hallucinations in schizophrenics when used in combination with neuroleptics.117 Higher doses of benzodiazepines, particularly oral diazepam, starting at 15 mg, may alleviate hallucinations, whereas lower doses serve to reduce agitation.117 If necessary, repeat dosing of diazepam may be given based on its elimination half-life of 44.2 hours.118 Although not well studied, it is likely that equivalent dosing of other benzodiazepines may be similarly effective. Withdrawal symptoms including hallucinations have occurred with the discontinuation of benzodiazepines after repeated dosing over a prolonged period.119 The synergistic interaction of opioids and benzodiazepines increases the risk of adverse cardiorespiratory events, and patients should be monitored closely.120,121



The treatment of opioid-induced hallucinations may be approached in a stepwise manner (Figure). At any point during treatment, the use of symptomatic management with opioid antagonists, antipsychotics, acetylcholinesterase inhibitors, or benzodiazepines may be considered. If hallucinations develop because of opioids, cessation of the opioids may be considered on an individualized basis. Opioid dose reduction, rotation, or altered routes of administration are the next steps in those patients not deemed candidates for opioid cessation. Furthermore, the use of multimodal pain management may be implemented with the use of adjuvant pharmacotherapeutics, rehabilitative and psychobehavioral treatments, or interventional modalities.

Back to Top | Article Outline


Opioid-induced hallucinations are an infrequent, yet significant potential adverse effect of pain therapy. It has been the goal of this review to raise awareness of this potential complication through a review of the literature and discussion of possible etiologic mechanisms, diagnosis, and treatment. Because prospective studies are lacking, which makes it difficult to draw definitive conclusions, a limitation of this review is that it primarily focuses on case reports. Patients may be reluctant to divulge the presence of hallucinations because of fears of being judged mentally unsound, and this should be kept in mind when patients discuss their displeasure with any opioid treatment program. As the rate of opioid consumption continues to increase, the rate of opioid-associated hallucinations may also increase. Future research focusing on the identification of genetically susceptible populations may hopefully decrease the incidence of opioid-induced hallucinations.

Back to Top | Article Outline


Name: Eellan Sivanesan, MD.

Contribution: This author helped prepare the manuscript.

Name: Melvin C. Gitlin, MD, FACPM.

Contribution: This author helped prepare the manuscript.

Name: Keith A. Candiotti, MD.

Contribution: This author helped prepare the manuscript.

This manuscript was handled by: Ken B. Johnson, MD.

Back to Top | Article Outline


1. Gupta S, Atcheson R. Opioid and chronic non-cancer pain. J Anaesthesiol Clin Pharmacol. 2013;29:612.
2. Trescot AM, Glaser SE, Hansen H, Benyamin R, Patel S, Manchikanti L. Effectiveness of opioids in the treatment of chronic non-cancer pain. Pain Physician. 2008;11:S181S200.
3. Birnbaum HG, White AG, Schiller M, Waldman T, Cleveland JM, Roland CL. Societal costs of prescription opioid abuse, dependence, and misuse in the United States. Pain Med. 2011;12:657667.
4. Hedegaard H, Chen LH, Warner MDrug-poisoning deaths involving heroin: United States, 2000–2013. NCHS data brief, no 190. Hyattsville, MD: National Center for Health Statistics, 2015.
5. Sehgal N, Colson J, Smith HS. Chronic pain treatment with opioid analgesics: benefits versus harms of long-term therapy. Expert Rev Neurother. 2013;13:12011220.
6. Kalso E, Edwards JE, Moore RA, McQuay HJ. Opioids in chronic non-cancer pain: systematic review of efficacy and safety. Pain. 2004;112:372380.
7. Papaleontiou M, Henderson CR Jr, Turner BJ, et al. Outcomes associated with opioid use in the treatment of chronic noncancer pain in older adults: a systematic review and meta-analysis. J Am Geriatr Soc. 2010;58:13531369.
8. Furlan AD, Sandoval JA, Mailis-Gagnon A, Tunks E. Opioids for chronic noncancer pain: a meta-analysis of effectiveness and side effects. CMAJ. 2006;174:15891594.
9. Brown RT, Zuelsdorff M, Fleming M. Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag. 2006;2:137146.
10. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11:S105S120.
11. Moore RA, McQuay HJ. Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids. Arthritis Res Ther. 2005;7:R1046R1051.
12. Eisenberg E, McNicol ED, Carr DB. Efficacy and safety of opioid agonists in the treatment of neuropathic pain of nonmalignant origin: systematic review and meta-analysis of randomized controlled trials. JAMA. 2005;293:30433052.
13. Tammela T, Kontturi M, Lukkarinen O. Postoperative urinary retention. I. Incidence and predisposing factors. Scand J Urol Nephrol. 1986;20:197201.
14. O’Riordan JA, Hopkins PM, Ravenscroft A, Stevens JD. Patient-controlled analgesia and urinary retention following lower limb joint replacement: prospective audit and logistic regression analysis. Eur J Anaesthesiol. 2000;17:431435.
15. Fénelon G, Mahieux F, Huon R, Ziégler M. Hallucinations in Parkinson’s disease: prevalence, phenomenology and risk factors. Brain. 2000;123(pt 4):733745.
16. Ohayon MM. Prevalence of hallucinations and their pathological associations in the general population. Psychiatry Res. 2000;97:153164.
17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM-5®). 2013.Washington, DC: American Psychiatric Publishing.
18. Daeninck PJ, Bruera E. Opioid use in cancer pain. Is a more liberal approach enhancing toxicity? Acta Anaesthesiol Scand. 1999;43:924938.
19. Okon TR, George ML. Fentanyl-induced neurotoxicity and paradoxic pain. J Pain Symptom Manage. 2008;35:327333.
20. Katz LY. Methadone-induced hallucinations. J Am Acad Child Adolesc Psychiatry. 1999;38:355356.
21. Keeley PW, Foster G, Whitelaw L. Hear my song: auditory hallucinations with tramadol hydrochloride. BMJ. 2000;321:1608.
22. Ito G, Kanemoto K. A case of topical opioid-induced delirium mistaken as behavioural and psychological symptoms of dementia in demented state. Psychogeriatrics. 2013;13:118123.
23. Rosebraugh CJ, Flockhart DA, Yasuda SU, Woosley RL. Visual hallucination and tremor induced by sertraline and oxycodone in a bone marrow transplant patient. J Clin Pharmacol. 2001;41:224227.
24. Moore TA. Musical hallucinations induced by oxycodone. Am J Geriatr Psychiatry. 2003;11:470.
25. Potter DR, Payne JP. Newer analgesics: with special reference to pentazocine. Br J Anaesth. 1970;42:186193.
26. Bruera E, Schoeller T, Montejo G. Organic hallucinosis in patients receiving high doses of opiates for cancer pain. Pain. 1992;48:397399.
27. Kalso E, Vainio A. Hallucinations during morphine but not during oxycodone treatment. Lancet. 1988;2:912.
28. Maddocks I, Somogyi A, Abbott F, Hayball P, Parker D. Attenuation of morphine-induced delirium in palliative care by substitution with infusion of oxycodone. J Pain Symptom Manage. 1996;12:182189.
29. De Nosaquo N. The hallucinatory effect of pentazocine (Talwin). JAMA. 1969;210:502.
30. Challoner KR, McCarron MM, Newton EJ. Pentazocine (Talwin) intoxication: report of 57 cases. J Emerg Med. 1990;8:6774.
31. Martin WR. Naloxone. Ann Intern Med. 1976;85:765768.
32. Waller SL, Bailey M. Hallucinations during morphine administration. Lancet. 1987;2:801.
33. Jellema JG. Hallucination during sustained-release morphine and methadone administration. Lancet. 1987;2:392.
34. Caraceni A, Martini C, De Conno F, Ventafridda V. Organic brain syndromes and opioid administration for cancer pain. J Pain Symptom Manage. 1994;9:527533.
35. Smith MT. Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol. 2000;27:524528.
36. Davies AN, Quinn T. Opioid-related musical hallucinations. J Pain Symptom Manage. 2005;29:327328.
37. Woodhouse A, Ward ME, Mather LE. Intra-subject variability in post-operative patient-controlled analgesia (PCA): is the patient equally satisfied with morphine, pethidine and fentanyl? Pain. 1999;80:545553.
38. Bruera E, Pereira J. Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain. Pain. 1997;69:199201.
39. Steinberg RB, Gilman DE, Johnson F III. Acute toxic delirium in a patient using transdermal fentanyl. Anesth Analg. 1992;75:10141016.
40. Gearing M. Roizen L, Shiraki H, Grcevic N, eds. Methadone maintenance in the treatment of heroin addicts in New York City: a ten year overview. Neurotoxicology. 1977:New York, NY: Raven Press, 7779.
41. Davis MP, Walsh D. Methadone for relief of cancer pain: a review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer. 2001;9:7383.
42. Abou Taam M, Boissieu Pd, Abou Taam R, Breton A, Trenque T. Drug-induced hallucination: a case/non case study in the French Pharmacovigilance Database. Eur J Psychiatry. 2015;29:2131.
43. Pellegrino P, Carnovale C, Borsadoli C, et al. Two cases of hallucination in elderly patients due to a probable interaction between flu immunization and tramadol. Eur J Clin Pharmacol. 2013;69:16151616.
44. MacEvilly M, O’Carroll C. Hallucinations after epidural buprenorphine. BMJ. 1989;298:928929.
45. Paraskevaides EC. Drug points: near fatal auditory hallucinations after buprenorphine. Br Med J (Clin Res Ed). 1988;296:214.
46. Sannidhya Varma SB, Basu D. Buprenorphine-induced psychotic symptoms: a case report. Prim Care Companion CNS Disord. 2013;15.
47. Kaptsan A, Telias D. Delirium due to buprenorphine therapy. Am J Case Reports. 2003;4:182185.
48. Seifert CF, Kennedy S. Meperidine is alive and well in the new millennium: evaluation of meperidine usage patterns and frequency of adverse drug reactions. Pharmacotherapy. 2004;24:776783.
49. Simopoulos TT, Smith HS, Peeters-Asdourian C, Stevens DS. Use of meperidine in patient-controlled analgesia and the development of a normeperidine toxic reaction. Arch Surg. 2002;137:8488.
50. Latta KS, Ginsberg B, Barkin RL. Meperidine: a critical review. Am J Ther. 2002;9:5368.
51. Geller RJ. Meperidine in patient-controlled analgesia: a near-fatal mishap. Anesth Analg. 1993;76:655657.
52. Pond SM, Kretschzmar KM. Effect of phenytoin on meperidine clearance and normeperidine formation. Clin Pharmacol Ther. 1981;30:680686.
53. Dimatteo L, Craig Van Dyke M. Meperidine-induced delirium. Am J Psychiatry. 1987;144:10621065.
54. Kolesnikov Y, Gabovits B, Levin A, Voiko E, Veske A. Combined catechol-O-methyltransferase and mu-opioid receptor gene polymorphisms affect morphine postoperative analgesia and central side effects. Anesth Analg. 2011;112:448453.
55. Gitlin MC, Taylor BK, Kalarickal PL, Lonseth ED. Does dysregulation of catechol-O-methyltransferase predispose to opioid-induced hallucinations? A report of a patient with microdeletion of chromosome 22 and opioid-associated hallucinations. Pain Med. 2007;8:8486.
56. Spanagel R, Herz A, Shippenberg TS. Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway. Proc Natl Acad Sci USA. 1992;89:20462050.
57. Johnson SW, North RA. Opioids excite dopamine neurons by hyperpolarization of local interneurons. J Neurosci. 1992;12:483488.
58. Tanda G, Pontieri FE, Di Chiara G. Cannabinoid and heroin activation of mesolimbic dopamine transmission by a common mu1 opioid receptor mechanism. Science. 1997;276:20482050.
59. Branford R, Droney J, Ross JR. Opioid genetics: the key to personalized pain control? Clin Genet. 2012;82:301310.
60. Lawlor PG. The panorama of opioid-related cognitive dysfunction in patients with cancer: a critical literature appraisal. Cancer. 2002;94:18361853.
61. Lötsch J. Opioid metabolites. J Pain Symptom Manage. 2005;29:S10S24.
62. Di Chiara G, Imperato A. Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharmacol Exp Ther. 1988;244:10671080.
63. Nugent FS, Penick EC, Kauer JA. Opioids block long-term potentiation of inhibitory synapses. Nature. 2007;446:10861090.
64. Dilts RP, Kalivas PW. Autoradiographic localization of mu-opioid and neurotensin receptors within the mesolimbic dopamine system. Brain Res. 1989;488:311327.
65. Meyer-Lindenberg A, Kohn PD, Kolachana B, et al. Midbrain dopamine and prefrontal function in humans: interaction and modulation by COMT genotype. Nat Neurosci. 2005;8:594596.
66. van Os J, Kenis G, Rutten BP. The environment and schizophrenia. Nature. 2010;468:203212.
67. Howes OD, Kapur S. The dopamine hypothesis of schizophrenia: version III—the final common pathway. Schizophr Bull. 2009;35:549562.
68. Mikell CB, McKhann GM, Segal S, McGovern RA, Wallenstein MB, Moore H. The hippocampus and nucleus accumbens as potential therapeutic targets for neurosurgical intervention in schizophrenia. Stereotact Funct Neurosurg. 2009;87:256265.
69. Kapur S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry. 2003;160:1323.
70. Braida D, Limonta V, Pegorini S, et al. Hallucinatory and rewarding effect of salvinorin A in zebrafish: kappa-opioid and CB1-cannabinoid receptor involvement. Psychopharmacology (Berl). 2007;190:441448.
71. Henquet C, Rosa A, Delespaul P, et al. COMT ValMet moderation of cannabis-induced psychosis: a momentary assessment study of ‘switching on’ hallucinations in the flow of daily life. Acta Psychiatr Scand. 2009;119:156160.
72. Diederich NJ, Fénelon G, Stebbins G, Goetz CG. Hallucinations in Parkinson disease. Nat Rev Neurol. 2009;5:331342.
73. Teeple RC, Caplan JP, Stern TA. Visual hallucinations: differential diagnosis and treatment. Prim Care Companion J Clin Psychiatry. 2009;11:2632.
74. Cummings JL, Miller BL. Visual hallucinations. Clinical occurrence and use in differential diagnosis. West J Med. 1987;146:4651.
75. Ali S, Patel M, Avenido J, Jabeen S, Riley WJ. Hallucinations: common features and causes. Curr Psychiatry. 2011;10:22.
76. Zanger UM, Schwab M. Cytochrome P450 enzymes in drug metabolism: regulation of gene expression, enzyme activities, and impact of genetic variation. Pharmacol Ther. 2013;138:103141.
77. Pelkonen O, Turpeinen M, Hakkola J, Honkakoski P, Hukkanen J, Raunio H. Inhibition and induction of human cytochrome P450 enzymes: current status. Arch Toxicol. 2008;82:667715.
78. Ross JR, Riley J, Taegetmeyer AB, et al. Genetic variation and response to morphine in cancer patients: catechol-O-methyltransferase and multidrug resistance-1 gene polymorphisms are associated with central side effects. Cancer. 2008;112:13901403.
79. Lee S, Kim DY, Kim JS, Kaur G, Lippmann S. Visual hallucinations following a left-sided unilateral tuberothalamic artery infarction. Innov Clin Neurosci. 2011;8:3134.
80. Hirschfeld RM, Russell JM. Assessment and treatment of suicidal patients. N Engl J Med. 1997;337:910915.
81. Mercadante S. Opioid rotation for cancer pain: rationale and clinical aspects. Cancer. 1999;86:18561866.
82. Friedman JH. The management of the levodopa psychoses. Clin Neuropharmacol. 1991;14:283295.
83. Factor SA, Molho ES, Podskalny GD, Brown D. Parkinson’s disease: drug-induced psychiatric states. Adv Neurol. 1995;65:115138.
84. Bauer SM, Schanda H, Karakula H, et al. Culture and the prevalence of hallucinations in schizophrenia. Compr Psychiatry. 2011;52:319325.
85. Schwartz LB, Metcalfe DD, Miller JS, Earl H, Sullivan T. Tryptase levels as an indicator of mast-cell activation in systemic anaphylaxis and mastocytosis. N Engl J Med. 1987;316:16221626.
86. Cherny N, Ripamonti C, Pereira J, et al.; Expert Working Group of the European Association of Palliative Care Network. Strategies to manage the adverse effects of oral morphine: an evidence-based report. J Clin Oncol. 2001;19:25422554.
87. Ripamonti C, Bruera E. CNS adverse effects of opioids in cancer patients. CNS Drugs. 1997;8:2137.
88. Harris JD. Management of expected and unexpected opioid-related side effects. Clin J Pain. 2008;24(suppl 10):S8S13.
89. Fine PG, Portenoy RK; Ad Hoc Expert Panel on Evidence Review and Guidelines for Opioid Rotation. Establishing ‘best practices’ for opioid rotation: conclusions of an expert panel. J Pain Symptom Manage. 2009;38:418425.
90. Osborne R, Joel S, Trew D, Slevin M. Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther. 1990;47:1219.
91. Mercadante S, Portenoy RK. Opioid poorly-responsive cancer pain. Part 3. Clinical strategies to improve opioid responsiveness. J Pain Symptom Manage. 2001;21:338354.
92. Quang-Cantagrel ND, Wallace MS, Magnuson SK. Opioid substitution to improve the effectiveness of chronic noncancer pain control: a chart review. Anesth Analg. 2000;90:933937.
93. Malhotra AK, Pinals DA, Adler CM, et al. Ketamine-induced exacerbation of psychotic symptoms and cognitive impairment in neuroleptic-free schizophrenics. Neuropsychopharmacology. 1997;17:141150.
94. de Stoutz ND1, Bruera E, Suarez-Almazor M. Opioid rotation for toxicity reduction in terminal cancer patients. J Pain Symptom Manage. 1995;10:378384.
95. Thomsen AB, Becker N, Eriksen J. Opioid rotation in chronic non-malignant pain patients. A retrospective study. Acta Anaesthesiol Scand. 1999;43:918923.
96. Choi YS, Billings JA. Opioid antagonists: a review of their role in palliative care, focusing on use in opioid-related constipation. J Pain Symptom Manage. 2002;24:7190.
97. Bruchas MR, Land BB, Chavkin C. The dynorphin/kappa opioid system as a modulator of stress-induced and pro-addictive behaviors. Brain Res. 2010;1314:4455.
98. Welch EB, Thompson DF. Opiate antagonists for the treatment of schizophrenia. J Clin Pharm Ther. 1994;19:279283.
99. Gunne LM, Lindström L, Terenius L. Naloxone-induced reversal of schizophrenic hallucinations. J Neural Transm. 1977;40:1319.
100. Clarke SF, Dargan PI, Jones AL. Naloxone in opioid poisoning: walking the tightrope. Emerg Med J. 2005;22:612616.
101. Farrell M. Opiate withdrawal. Addiction. 1994;89:14711475.
102. Zilles D, Zerr I, Wedekind D. Successful treatment of musical hallucinations with the acetylcholinesterase inhibitor donepezil. J Clin Psychopharmacol. 2012;32:422424.
103. Fabbrini G, Barbanti P, Aurilia C, Pauletti C, Lenzi GL, Meco G. Donepezil in the treatment of hallucinations and delusions in Parkinson’s disease. Neurol Sci. 2002;23:4143.
104. Patel SS, Attard A, Jacobsen P, Shergill S. Acetylcholinesterase inhibitors (AChEI’s) for the treatment of visual hallucinations in schizophrenia: a case report. BMC Psychiatry. 2010;10:68.
105. Slatkin N, Rhiner M. Treatment of opioid-induced delirium with acetylcholinesterase inhibitors: a case report. J Pain Symptom Manage. 2004;27:268273.
106. Estfan B, Yavuzsen T, Davis M. Development of opioid-induced delirium while on olanzapine: a two-case report. J Pain Symptom Manage. 2005;29:330332.
107. Wines JD Jr, Weiss RD. Opioid withdrawal during risperidone treatment. J Clin Psychopharmacol. 1999;19:265267.
108. Schreiber S, Backer MM, Weizman R, Pick CG. Augmentation of opioid induced antinociception by the atypical antipsychotic drug risperidone in mice. Neurosci Lett. 1997;228:2528.
109. Ondo WG, Tintner R, Voung KD, Lai D, Ringholz G. Double-blind, placebo-controlled, unforced titration parallel trial of quetiapine for dopaminergic-induced hallucinations in Parkinson’s disease. Mov Disord. 2005;20:958963.
110. Goetz CG, Fan W, Leurgans S. Antipsychotic medication treatment for mild hallucinations in Parkinson’s disease: positive impact on long-term worsening. Mov Disord. 2008;23:15411545.
111. Ondo WG, Levy JK, Vuong KD, Hunter C, Jankovic J. Olanzapine treatment for dopaminergic-induced hallucinations. Mov Disord. 2002;17:10311035.
112. Coletti Moja M, Milano E, Gasverde S, Gianelli M, Giordana MT. Olanzapine therapy in hallucinatory visions related to Bonnet syndrome. Neurol Sci. 2005;26:168170.
113. Fleischhacker WW, Eerdekens M, Karcher K, et al. Treatment of schizophrenia with long-acting injectable risperidone: a 12-month open-label trial of the first long-acting second-generation antipsychotic. J Clin Psychiatry. 2003;64:12501257.
114. Yee JD, Berde CB. Dextroamphetamine or methylphenidate as adjuvants to opioid analgesia for adolescents with cancer. J Pain Symptom Manage. 1994;9:122125.
115. Webster L, Andrews M, Stoddard G. Modafinil treatment of opioid-induced sedation. Pain Med. 2003;4:135140.
116. Bruera E, Watanabe S. Psychostimulants as adjuvant analgesics. J Pain Symptom Manage. 1994;9:412415.
117. Lingjaerde O. Benzodiazepines in the treatment of schizophrenia: an updated survey. Acta Psychiatr Scand. 1991;84:453459.
118. Greenblatt DJ, Harmatz JS, Friedman H, Locniskar A, Shader RI. A large-sample study of diazepam pharmacokinetics. Ther Drug Monit. 1989;11:652657.
119. Bergman I, Steeves M, Burckart G, Thompson A. Reversible neurologic abnormalities associated with prolonged intravenous midazolam and fentanyl administration. J Pediatr. 1991;119:644649.
120. Gross JB, Bailey PL, Caplan R, et al. Practice guidelines for sedation and analgesia by non-anesthesiologists: a report by the American Society of Anesthesiologists Task Force on Sedation and Analgesia by Non-Anesthesiologists. Anesthesiology. 1996;84:459471.
121. Vinik HR, Bradley EL Jr, Kissin I. Triple anesthetic combination: propofol-midazolam-alfentanil. Anesth Analg. 1994;78:354358.
Copyright © 2016 International Anesthesia Research Society