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Myoclonus Secondary to Withdrawal from Transdermal Fentanyl

Case Report and Literature Review

      Abstract

      Myoclonus is a common and well-described adverse effect of opioids. Most cases reported in the literature have been associated with opioid administration, rather than with opioid withdrawal. We describe a case of myoclonus secondary to withdrawal from transdermal fentanyl. We review the literature regarding myoclonus related to opioid therapy (opioid-induced myoclonus) and withdrawal (opioid withdrawal myoclonus), and discuss possible mechanisms and therapies for these phenomena.

      Keywords

      Introduction

      Myoclonus is a relatively common adverse effect of opioid therapy.
      • Caviness J.N.
      Myoclonus.
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      Typically observed during opioid administration, and particularly with high-dose therapy, myoclonus is conventionally thought to be a direct neurotoxic effect of opioid analgesics. Several possible mechanisms have been postulated to explain how opioids might induce myoclonus, but the precise pathophysiology remains poorly understood.
      • Caviness J.N.
      Myoclonus.
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      • Pranzatelli M.R.
      • Snodgrass S.R.
      The pharmacology of myoclonus.
      • Fahn S.
      • Marsden C.D.
      • Van Woert M.H.
      Definition and classification of myoclonus.
      • Lauterbach E.C.
      Hiccup and apparent myoclonus after hydrocodone review of the opiate-related hiccup and myoclonus literature.
      Less commonly, myoclonus has been observed in association with withdrawal from opioid therapy, and this phenomenon raises still more questions about the relationship between opioids and myoclonus.
      • Lauterbach E.C.
      Hiccup and apparent myoclonus after hydrocodone review of the opiate-related hiccup and myoclonus literature.
      In this article, we report an unusual case of myoclonus associated with withdrawal from transdermal fentanyl. We review the literature on myoclonus related to both opioid administration (opioid-induced myoclonus, or OIM) and withdrawal (opioid withdrawal myoclonus, or OWM). Finally, we discuss possible implications of the phenomenon of OWM for our understanding and treatment of opioid-related myoclonus generally.

      Case Report

      A 28-year-old woman was admitted to the University of Pittsburgh Medical Center (UPMC) for management of presumed opioid-induced ileus, and an unusual fentanyl withdrawal syndrome. The patient had undergone isolated small bowel transplantation at UPMC two months prior to admission, following a postpartum mid-gut volvulus requiring massive small bowel resection and permanent total parenteral nutrition (TPN) four months prior to transplantation.
      The patient's course prior to small bowel transplantation had been remarkable for treatment with fentanyl associated with the development of physical dependence. In the postoperative period following her native enterectomy, the patient had been started on transdermal fentanyl (Duragesic Transdermal System, Janssen) at a dose of 100 μg/hr for post-operative pain. The transdermal fentanyl was continued following her discharge from the hospital, and her pain remained well controlled. However, numerous attempts at discontinuing the drug resulted in a withdrawal syndrome consisting of a sense of “skin crawling,” followed by sudden uncontrollable rhythmic jerking movements of her arms and legs. This syndrome first occurred when the patient abruptly discontinued transdermal fentanyl after her prescription ran out; the jerking movements became severe and sustained enough to prompt an emergency room visit. In the emergency room, the patient was given intravenous meperidine and the Duragesic patch was restarted, resulting in immediate resolution of her symptoms.
      These same symptoms also occurred every third day following application of the transdermal fentanyl patch. In response, the patient's physicians increased the dose frequency of the transdermal fentanyl patch to 48-hr—rather than 72-hr—intervals. The symptoms subsequently abated. At no time did the patient manifest other, more typical symptoms of opioid withdrawal.
      Following isolated intestinal transplantation, the patient was continued on transdermal fentanyl, and was able to be weaned down to a dose of 75 μg/hr patch every 48 hrs. Her postoperative course was remarkable for intermittent nausea and vomiting. In the two months following her transplantation, the patient was hospitalized twice for severe exacerbations of nausea and vomiting, which were believed to result from an ileus of unclear etiology. She underwent multiple diagnostic studies which proved unrevealing. She was treated conservatively with some improvement, although she still suffered from daily chronic symptoms.
      Two months after successful graft implantation, the patient returned back to her distant home state. A few weeks later, she was scheduled to return to UPMC for a routine outpatient ileoscopy and biopsy to monitor for cellular rejection. However, during the week prior to this scheduled testing, the patient developed an exacerbation of her nausea and vomiting with progressive abdominal discomfort. Her attending surgeon suspected opioid-induced ileus, and admitted the patient with the intent to withdraw her from fentanyl in a supervised setting, as well as to complete her planned diagnostic evaluation.
      There was no history of seizure disorder or other significant medical problems. The patient's other medications at the time of this admission included tacrolimus, sirolimus, prednisone, magnesium gluconate, zinc sulfate, trimethoprim/sulfamethoxazole, nystatin, omeprazole, and daclizumab. Her initial physical examination was unremarkable, and laboratory testing revealed normal tacrolimus levels and no evidence of renal insufficiency or electrolyte abnormalities.
      On the first hospital day, the transdermal fentanyl was discontinued. The Palliative Care and Chronic Pain Service at UPMC was consulted at that time, and recommended beginning lorazepam and clonidine around the clock. Approximately 6 hours after discontinuation of transdermal fentanyl, the patient began experiencing a vague sensation of “skin crawling.” Approximately 12 hours after drug discontinuation, myoclonic jerks of both arms and legs began and became progressively more severe. These abnormal movements occurred at rest and were generalized and repetitive, and not associated with other abnormal movements or focal neurologic signs or symptoms. There was no alteration in mental status or other evidence of generalized seizure activity. The patient was given additional intravenous lorazepam with minimal improvement in symptoms. The primary service also attempted trials of haloperidol and diphenhydramine, which caused sedation and helped the patient to rest, but had minimal effect upon her symptoms.
      The myoclonus gradually abated and resolved completely by 36 hours following the discontinuation of transdermal fentanyl. However, on the second hospital day the patient also developed increasing restlessness, agitation, tachycardia, and abdominal pain, which continued through the third hospital day. Lorazepam and clonidine were continued. By the end of the third hospital day, both the myoclonus and the more typical symptoms of opioid withdrawal had resolved. The patient was left with insomnia that was refractory to various sedative-hypnotic medications. Her intermittent nausea and vomiting remained unchanged. Subsequently, her gastrointestinal radiologic imaging and endoscopic studies revealed a pinhole jejunojejunostomy anastomotic stricture, which was successfully dilated endoscopically. Following the procedure, the patient's nausea and vomiting as well as her insomnia resolved, and she was discharged home on the sixth hospital day with no changes in any of the immunosuppressive or other medications.
      After discharge, the patient continued to experience rare myoclonic jerks for 2–3 more days, and her insomnia persisted for approximately two more weeks before finally resolving without further treatment.

      Discussion

      Myoclonus is a descriptive term signifying “sudden, brief, shocklike, involuntary movements caused by muscular contractions or inhibitions.”
      • Caviness J.N.
      Myoclonus.
      Myoclonus is a not a single clinical entity, but rather a group of syndromes of diverse cause, neuroanatomic localization, and pathogenesis.
      • Caviness J.N.
      Myoclonus.
      • Pranzatelli M.R.
      • Snodgrass S.R.
      The pharmacology of myoclonus.
      The various forms of myoclonus have been conceptualized under four principal categories: physiologic, epileptic, essential, and symptomatic.
      • Fahn S.
      • Marsden C.D.
      • Van Woert M.H.
      Definition and classification of myoclonus.
      Opioid-related myoclonus falls under the category of symptomatic myoclonus, and resembles clinical syndromes associated with other toxic-metabolic conditions.
      Myoclonus is a well-described and relatively common adverse effect of opioid use.
      • Caviness J.N.
      Myoclonus.
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      Its reported incidence in various studies ranges from 2.7% to 87%.
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      Morphine, hydromorphone, meperidine, methadone, and hydrocodone have all been reported to cause myoclonus,
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      • Lauterbach E.C.
      Hiccup and apparent myoclonus after hydrocodone review of the opiate-related hiccup and myoclonus literature.
      • Sarhill N.
      • Davis M.P.
      • Walsh D.
      • Nouneh C.
      Methadone-induced myoclonus in advanced cancer.
      which has usually been described as a toxic effect of high-dose or prolonged opioid therapy.
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      • Hagen N.
      • Swanson R.
      Strychnine-like multifocal myoclonus and seizures in extremely high-dose opioid administration treatment strategies.
      • MacDonald N.
      • Der L.
      • Allan S.
      • Champion P.
      Opioid hyperexcitability the application of alternate opioid therapy.
      • Bruera E.
      • Pereira J.
      Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain.
      With respect to the present case discussion, several reports in the literature describe the occurrence of myoclonus specifically during use of fentanyl in both adult
      • Bruera E.
      • Pereira J.
      Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain.
      • Kiyama S.
      • Yoshikawa T.
      Persistent intraoperative myoclonus during propofol-fentanyl anaesthesia.
      • Petzinger G.
      • Mayer S.A.
      • Przedborski S.
      Fentanyl-induced dyskinesias.
      • Adair J.C.
      • El-Nachef A.
      • Cutler P.
      Fentanyl neurotoxicity.
      • Stuerenburg H.J.
      • Claassen J.
      • Eggers C.
      • Hansen H.C.
      Acute adverse reaction to fentanyl in a 55 year old man.
      and pediatric
      • Bergman I.
      • Steeves M.
      • Burckart G.
      • Thompson A.
      Reversible neurologic abnormalities associated with prolonged intravenous midazolam and fentanyl administration.
      patients. Multiple case reports in the anesthesia literature have also documented the occurrence of diverse movement disorders, including myoclonus, during fentanyl administration for operative anesthesia.
      • Sprung J.
      • Schedewie H.K.
      Apparent focal motor seizure with a Jacksonian march induced by fentanyl a case report and review of the literature.
      Although myoclonus occurring during acute opioid administration has been well described, it has not often been observed as a primary manifestation of opioid withdrawal in general, or of withdrawal from fentanyl in particular. In a review of the literature on opioid-related myoclonus (ORM), Lauterbach distinguished between opioid-induced myoclonus (OIM) and opioid withdrawal myoclonus (OWM).
      • Lauterbach E.C.
      Hiccup and apparent myoclonus after hydrocodone review of the opiate-related hiccup and myoclonus literature.
      In this review, only two case reports on OWM were cited, one involving use of epidural diamorphine,
      • Jayawardena B.
      • Hill D.J.
      Myoclonic spasms after epidural diamorphine infusion.
      and one following use of meperidine.
      • Reutens D.C.
      • Stewart-Wynne E.G.
      Norpethidine induced myoclonus in a patient with renal failure.
      It is notable, however, that only the case of epidural diamorphine-related myoclonus
      • Jayawardena B.
      • Hill D.J.
      Myoclonic spasms after epidural diamorphine infusion.
      was clearly related to withdrawal. The cited case of meperidine
      • Reutens D.C.
      • Stewart-Wynne E.G.
      Norpethidine induced myoclonus in a patient with renal failure.
      actually involved myoclonus occurring 36 hours after meperidine administration in a patient with renal failure; in this case myoclonus was attributed not to withdrawal from meperidine, but to neurotoxic effects of its metabolite normeperidine.
      Regarding myoclonus related specifically to fentanyl withdrawal, a MEDLINE search turned up citations only in the pediatric literature. Lane and colleagues described a cluster of 5 children, ranging from 6 months to 3.5 years of age, cared for in a pediatric intensive care unit.
      • Lane J.C.
      • Tennison M.B.
      • Lawless S.T.
      • et al.
      Movement disorder after withdrawal of fentanyl infusion.
      These children all acutely developed severe transient myoclonus and other movement disorders within 48 hours following tapering of intravenous fentanyl infusions. Notably, more typical opioid withdrawal symptoms (e.g., sweat-ing, rhinorrhea, yawning, pupillary dilatation, gooseflesh, diarrhea) were absent in these patients, and irritability and insomnia were prominent and persistent associated symptoms. Other groups have also observed various movement disorders, although not always including classic myoclonus, related to withdrawal from fentanyl infusions in pediatric ICU patients.
      • French J.P.
      • Nocera M.
      Drug withdrawal symptoms in children after continuous infusions of fentanyl.
      • Katz R.
      • Kelly H.W.
      • His A.
      Prospective study on the occurrence of withdrawal in critically ill children who receive fentanyl by continuous infusion.
      Otherwise, the available literature contains no citations of similar occurrences in adult patients.
      The rarity of myoclonus as a manifestation of opioid withdrawal raises questions about the present case, and about the mechanisms of opioid-related myoclonus in general. Did our patient possess any unique clinical features that might have predisposed to the development of myoclonus as a symptom of opioid withdrawal? She had no obvious predisposing medical conditions, but she was on multiple medications at least some of which are known to have neurotoxic effects. The related immunosuppressants tacrolimus and sirolimus are both associated with adverse neurologic effects, including seizures and movement disorders. For example, the incidence of tremor in tacrolimus- and sirolimus-treated patients is reportedly as high as 50% and 30%, respectively. It is conceivable that these medications might have somehow potentiated the opioid-related abnormal movement disorder in our patient. Alternatively, the fentanyl might have somehow acted to influence the expression of primary neurologic toxicities of the immunosuppressants in this case. The mechanisms for these potential causes, however, are unclear.
      One might argue that some aspect of this patient's opioid therapy might be responsible for her development of myoclonus with opioid withdrawal. It is true that transdermal fentanyl is not routinely used in postoperative patients generally, and particularly at relatively high doses and for prolonged time periods. This patient was also on a more frequent (48 hr) than usual dose schedule of the Duragesic patch. Furthermore, during her supervised withdrawal from transdermal fentanyl, neither lower doses nor alternative forms of fentanyl, nor alternative opioid agonists were given to ameliorate the withdrawal symptoms.
      The patient's primary physicians made these treatment decisions for a number of reasons. The patient did have significant persistent postoperative pain, and in the setting of chronic intestinal failure and small bowel transplantation requiring prolonged bowel rest, parenteral opioids such as transdermal fentanyl are rational and frequently used. The patient's postoperative pain persisted but eventually did abate; however, it was the consistent repetitive occurrence of myoclonus at 48 hours following fentanyl patch application that prompted continuation of the drug beyond the immediate postoperative period and the increase in its dose frequency. Finally, the patient's primary surgeons opted against more gradual dose tapering or opioid rotation, mainly because of concern that opioid-induced ileus or obstruction could have been jeopardizing the patient's small bowel graft.
      While these aspects of this patient's case were somewhat unusual, there is no reason to believe that they caused the myoclonus observed, or diminished the potential clinical implications of this phenomenon. Transdermal fentanyl is not an uncommonly used medication in small bowel transplant patients with persistent postoperative pain. Myoclonus occurred relatively early into the patient's fentanyl therapy and was a consistent occurrence with consistent response to the resumption of fentanyl. The myoclonus observed with previous Duragesic patch changes and discontinuation was similar in all respects to that observed with the supervised complete withdrawal of the fentanyl. Thus we believe that withdrawal from transdermal fentanyl, not the patient's medical management per se, was responsible for the myoclonus observed, and that this phenomenon has several possible implications.
      It is remarkable that our patient did not manifest more typical opioid withdrawal symptoms and signs until much later during her planned opioid abstinence; myoclonus constituted the cardinal manifestation of withdrawal. This situation, as well as the prominence of insomnia as a later manifestation, is similar to the observations of Lane and colleagues.
      • Lane J.C.
      • Tennison M.B.
      • Lawless S.T.
      • et al.
      Movement disorder after withdrawal of fentanyl infusion.
      The similarity of these observations might suggest the existence of a withdrawal syndrome unique to fentanyl, although the phenomena observed might just as well have been idiosyncratic occurrences. There is no obvious reason why fentanyl should behave differently from other opioid μ-agonists. At the least, however, these observations offer some data that might be relevant to our understanding of opioid-related myoclonus in general.
      The pathophysiology of opioid-related myoclonus in general is poorly understood, and the occurrence of ORM related to withdrawal—as in the present case report—raises further questions about the mechanisms involved. Several hypotheses have been put forth to explain the occurrence of myoclonus induced by opioid administration. Various opioid compounds and metabolites (e.g., meperidine, normeperidine, morphine-3-glucuronide, hydromorphone metabolites) have been postulated to have direct neuro-excitatory, proconvulsant effects.
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      • Hagen N.
      • Swanson R.
      Strychnine-like multifocal myoclonus and seizures in extremely high-dose opioid administration treatment strategies.
      • MacDonald N.
      • Der L.
      • Allan S.
      • Champion P.
      Opioid hyperexcitability the application of alternate opioid therapy.
      • Bruera E.
      • Pereira J.
      Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain.
      Several authors believe that neuro-excitatory metabolites of opioids accumulate with chronic or high dosing, and are primarily responsible, through non-μ receptor activity, for the occurrence of myoclonus.
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      • Bruera E.
      • Pereira J.
      Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain.
      However, this theory does not explain the occurrence of myoclonus with fentanyl, which is typically believed to be devoid of active metabolites and non-μ receptor effects.
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      The precise pathophysiologic mechanisms for these neuro-excitatory effects, furthermore, are not known. Some evidence suggests that opioid-induced myoclonus may be indirectly mediated through glutamate activation of N-methyl-D-aspartate (NMDA) receptors.
      • MacDonald N.
      • Der L.
      • Allan S.
      • Champion P.
      Opioid hyperexcitability the application of alternate opioid therapy.
      Various authors believe that myoclonus and other neuro-excitatory effects might result from opioid-induced disinhibition of neural pathways at the level of the central nervous system (CNS) cortex
      • MacDonald N.
      • Der L.
      • Allan S.
      • Champion P.
      Opioid hyperexcitability the application of alternate opioid therapy.
      • Kauffman R.E.
      Fentanyl, fads, and folly who will adopt the therapeutic orphans?.
      or the spinal motor neuron, where glycine is felt to be an important inhibitory neurotransmitter.
      • Hagen N.
      • Swanson R.
      Strychnine-like multifocal myoclonus and seizures in extremely high-dose opioid administration treatment strategies.
      Opioids may antagonize post-synaptic inhibitory glycine and gamma-amino-butyric acid (GABA) activity in the spinal cord, thereby leading to depolarization of spinal cord neurons and myoclonus.
      • Mercadante S.
      Dantrolene treatment of opioid-induced myoclonus.
      Others have suggested that serotonergic and GABAergic pathways in the brainstem play a crucial role in opioid-induced rigidity states such as myoclonus.
      • Weinger M.B.
      • Sanford T.J.
      • Smith N.T.
      Do dopaminergic drugs really prevent opioid-induced rigidity?.
      Opioids are also known to possess dopamine antagonist activity and endogenous opioids have been shown to be involved in basal ganglia disorders, and thus synthetic opioids might contribute to movement disorders through extrapyramidal pathways.
      • Lane J.C.
      • Tennison M.B.
      • Lawless S.T.
      • et al.
      Movement disorder after withdrawal of fentanyl infusion.
      • Mercadante S.
      Dantrolene treatment of opioid-induced myoclonus.
      It seems clear that the myoclonus and other neuro-excitatory effects of opioids probably involve multiple physiologic pathways and receptor systems.
      Since myoclonus resulting from opioid withdrawal—as opposed to acute opioid administration—has been more rarely reported, its pathophysiology is even more poorly understood. Commenting on the case report of fentanyl withdrawal by Lane,
      • Lane J.C.
      • Tennison M.B.
      • Lawless S.T.
      • et al.
      Movement disorder after withdrawal of fentanyl infusion.
      Kauffman
      • Kauffman R.E.
      Fentanyl, fads, and folly who will adopt the therapeutic orphans?.
      postulated that the opioid withdrawal described might result from a temporary imbalance among excitatory and inhibitory pathways regulating motor activity in the CNS. Prolonged exposure to exogenous opioid agonists may lead to a selective “down-regulation” of opioid receptors that are part of these inhibitory pathways, and subsequently to a temporarily reduced activity of the inhibitory pathway after withdrawal of the exogenous agonist.
      • Kauffman R.E.
      Fentanyl, fads, and folly who will adopt the therapeutic orphans?.
      This reduction or “desensitization” of inhibitory activity might then result in myoclonus and other motor disorders. Bruera and Pereira hypothesize that neuro-excitatory effects of acute opioid administration are naloxone-responsive and mediated by opioid receptors, but that neuro-excitatory effects occurring in chronic opioid administration are non-responsive to naloxone, and due to the activation of non-opioid receptors by active opioid metabolites.
      • Bruera E.
      • Pereira J.
      Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain.
      They cite the theory that in patients on chronic opioids, naloxone could cause seizures by “blocking the depressant effects of the circulating opioids and allowing the expression of the convulsant activity of active metabolites to manifest”.
      • Bruera E.
      • Pereira J.
      Acute neuropsychiatric findings in a patient receiving fentanyl for cancer pain.
      If this theory is correct, then one would expect the same response from simple withdrawal from opioid, without naloxone antagonism. Adrenergic excitation also is clearly known to occur in opioid withdrawal, and is the basis for the widespread use of drugs like clonidine in the prevention and treatment of opioid withdrawal, although the precise mechanisms responsible for this hyperadrenergic state are unclear.
      • Carr D.B.
      • Todres I.D.
      Fentanyl infusion in critically ill children.
      It is furthermore not clear whether adrenergic excitation contributes in some way to myoclonus.
      The fact that myoclonus may occur with both acute opioid administration (OIM) and opioid withdrawal (OWM), and that the clinical manifestations of this syndrome are similar in both situations, raises several important issues. First, it highlights both the central physiologic role of opioid ligands in normal and abnormal motor activity, and the potential for opioid therapy to disrupt the complex balance between excitatory and inhibitory motor pathways. At the same time, it highlights the limitations in our knowledge of what perturbs this complex balance; how and when is there too much opioid activity, and how and when is there too little? From a practical, clinical standpoint, it raises a question perhaps not often considered in the past: if myoclonus occurs in the setting of opioid use, is it an effect of opioid overdose or withdrawal? One could ask, for instance, whether in some cases of apparent OIM the observed myoclonus might be related to temporary withdrawal, resulting from naturally-decaying serum concentrations between administered doses. Although we do not have direct evidence of this (e.g., serum measurements of fentanyl), it is conceivable given the known potential for plasma fentanyl concentrations to decline 48 hours following application of the Duragesic patch.
      • Jeal W.
      • Benfield B.
      Transdermal fentanyl a review of its pharmacological properties and therapeutic efficacy in pain control.
      Several therapeutic implications follow. First, while opioid discontinuation or rotation is commonly recommended as a response to the occurrence of opioid-related myoclonus,
      • Hagen N.
      • Swanson R.
      Strychnine-like multifocal myoclonus and seizures in extremely high-dose opioid administration treatment strategies.
      • MacDonald N.
      • Der L.
      • Allan S.
      • Champion P.
      Opioid hyperexcitability the application of alternate opioid therapy.
      clinicians should also consider the possibility that myoclonus might be caused by withdrawal rather than overdose; in this case, the appropriate response might not be to discontinue the current opioid. For myoclonus secondary to opioid withdrawal, as in the present case, the most appropriate intervention might be to reintroduce and more slowly taper the particular opioid in question.
      Furthermore, when myoclonus occurs in the setting of opioid administration, clinicians should also assess for the presence of any other CNS-active medications that might act upon receptors implicated in opioid-active inhibitory motor pathways. There is empirical evidence, for example, that morphine-related myoclonus occurs more frequently in patients treated with antidepressant, antipsychotic, antiemetic, and nonsteroidal anti-inflammatory (NSAID) medications.
      • Potter J.M.
      • Reid D.B.
      • Shaw R.J.
      • Hackett P.
      • Hickman P.E.
      Myoclonus associated with treatment with high doses of morphine the role of supplemental drugs.
      These adjuvant medications might influence opioid-mediated myoclonus through their activity on serotonergic, dopaminergic, and other pathways discussed above, and discontinuation of these drugs might conceivably be of benefit. In the case we described, the immunosuppressant medications in particular may have played a role in potentiating myoclonus, and some consideration could have been given to withholding these drugs.
      Treatment options other than opioid discontinuation and rotation have not been rigorously evaluated. Most authors recommend empiric therapy with benzodiazepines, in part based upon the observation of their efficacy in management of other forms of myoclonus, epileptic myoclonus in particular.
      • Caviness J.N.
      Myoclonus.
      • Eisele J.H.
      • Grigsby E.J.
      • Dea G.
      Clonazepam treatment of myoclonic contractions associated with high-dose opioids case report.
      Benzodiazepines would also be of theoretical benefit if indeed GABAergic pathways are important in opioid-related myoclonus. Several authors recommend clonazepam,
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      • Eisele J.H.
      • Grigsby E.J.
      • Dea G.
      Clonazepam treatment of myoclonic contractions associated with high-dose opioids case report.
      whereas others have reported better experience with lorazepam.
      • Hagen N.
      • Swanson R.
      Strychnine-like multifocal myoclonus and seizures in extremely high-dose opioid administration treatment strategies.
      In the case presented for discussion here, lorazepam seemed to have had little beneficial effect. The muscle relaxant dantrolene has been reported to be effective in terminally-ill patients with opioid-induced myoclonus,
      • Mercadante S.
      Dantrolene treatment of opioid-induced myoclonus.
      and anticonvulsants like valproic acid, and the GABA agonist baclofen, have also been used.
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      Long-acting opioids such as methadone are widely used in managing withdrawal symptoms in the setting of opioid detoxification, and might be a rational alternative for managing myoclonus related to opioid withdrawal. It deserves mention, however, that myoclonus has also been reported in association with methadone,
      • Sarhill N.
      • Davis M.P.
      • Walsh D.
      • Nouneh C.
      Methadone-induced myoclonus in advanced cancer.
      and in one case could arguably have been precipitated by withdrawal from methadone.
      • Manfredi P.L.
      • Gonzales G.R.
      • Payne R.
      Reversible spastic paraparesis induced by high-dose intravenous methadone.
      At the present time, the optimal treatment of opioid-related myoclonus has not been firmly established. Mild cases may require no treatment other than observation or opioid rotation.
      • Mercadante S.
      Pathophysiology and treatment of opioid-related myoclonus in cancer patients.
      Most experts would probably recommend use of benzodiazepines in more severe cases, reserving baclofen or anticonvulsants for the most severe or refractory myoclonus. Establishing the optimal treatment and improving our understanding of the underlying mechanisms of opiate-related myoclonus awaits further research.

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