Rigidity, catalepsy, akathisia, tremors, and myoclonus are all clinical side effects associated with the use of opioids [1-5]. Myoclonus may be associated occasionally with opioid therapy in patients with cancer pain, and appears to be dose-related in an unpredictable manner. Hyperalgesia and myoclonus from large doses of morphine administered either intraspinally or intravenously have been described [6,7]. We describe two cases in which dantrolene was used successfully to treat contractions associated with opioid therapy.
A 67-yr-old man with prostatic cancer and diffused bone metastases was referred to our pain relief unit. He was receiving slow-release morphine in doses of 60 mg a day with acceptable pain relief (visual analog scale of 0-10 cm [VAS], less than 4) and moderate sedation. However, he was complaining of severe weakness and sudden, frequent, diffuse, and uncontrollable twitching and jerking of the muscles, especially during the night. Smaller opioid doses (morphine 30 mg/day) reduced these episodes but poor pain control resulted (VAS 8). Other alternative strong opioids were not available. A trial of dantrolene was proposed maintaining the previous dosage of morphine. Specifically, oral dantrolene 50 mg three times daily and slow-release morphine 30 mg three times daily were started. Pain relief (VAS less than 4) was again achieved within 24 h and an evident reduction of frequency, intensity, and duration of muscle contractions was observed. No important side effects were reported.
In the following days, morphine doses were titrated up to 120 mg/day to maintain good pain relief without changing the dantrolene dose. The myoclonic contractions were limited and well accepted by the patient who died 22 days after starting dantrolene.
A 61-yr-old man, with basal cell carcinoma of the skin and diffuse bone metastases, was referred to the outpatient pain clinic. He had been treated by morphine but had to stop the treatment because of intolerable side effects. He then received methadone, the dose of which was gradually increased to achieve analgesia. After 1 wk of treatment, his pain was acceptably controlled with methadone 24 mg/day (in three doses) and a rescue dose of 8 mg. He experienced moderate sedation and sudden myoclonic activity lasting a few seconds and exclusively presenting after 8:00 PM. These symptoms persisted for 1 mo after therapy. Dantrolene 50 mg was prescribed to be taken once a day at 6:00 PM. Muscle contractions ceased and no adverse effects were reported. This successful treatment was continued and no other muscular disturbances were observed until the patient's death.
Many authors speculate that neuroexitatory metabolites of morphine may be responsible for the simultaneous development of myoclonus and a hyperalgesic state in cancer pain patients treated by high doses of opioids [7-9]. Morphine 3-glucuronide (M3G) may antagonize the analgesic effects of morphine and result in hyperalgesia and myoclonus . A high M3G/morphine 6-glucuronide (M6G) ratio is associated with paradoxical pain, a term coined to describe pain unrelieved or worsened by morphine administration . However, the dose of morphine used in this case cannot be considered large, and pain control was good. Moreover, any increase in the morphine dose was followed by a good pain relief until death. Blood samples for morphine plasma concentration analysis were not available. However, M3G/M6G ratios observed in morphine-resistant patients were similar to the values reported in patients with well controlled pain . The role of morphine metabolites as excitatory drugs remains controversial. Paroxysmal depolarization of spinal cord neurons after high doses of opioids may be linked to the antagonism of postsynaptic gamma -aminobutyric acid and glycine inhibition through a nonopiate mechanism resembling that of strychnine. Therefore, morphine may act by reducing postsynaptic inhibition through an antiglycinergic effect .
Myoclonus occurs after the administration of either fentanyl or sufentanil without showing cortical seizure activity . Opioids commonly produce a spectrum of movement abnormalities, including rigidity, myoclonus, and seizures. An effect on the limbic system, as well as on serotonergic pathways, may be a mechanism of narcotic-induced myoclonus . Opioids possess a dopamine antagonist activity, as shown by a release of prolactin due to a complex action on the hypothalamus-hypophysis axis . Extensive studies of basal ganglia neurophysiology suggest that muscular rigidity is produced by mu receptors located on interneurons in the caudate nucleus. Regardless of the etiology, the final common pathway of morphine resembles the motor abnormalities observed in Parkinson's disease and extrapyramidal drug reaction . However, the neuropharmacology of opioid-induced muscular disorders remains unclear . A variety of drugs cause abnormal muscular movements due to their action on the extrapyramidal motor system. Adjuvant neuroleptic drugs with antidopaminergic activity, such as phenothiazines and butyrophenones, frequently used in palliative care, may worsen the clinical picture, probably by blocking dopamine receptors in the basal ganglia. This class of drugs had previously been stopped in the cases here reported.
A specific treatment to control myoclonus should be considered when alternate opioid therapy is unavailable or not effective .
Benzodiazepines, such as clonazepam and nitrazepam, have been proposed to treat myoclonus induced by opioids . This is consistent with studies that support a GABAergic mechanism . However, a combination of opioids and benzodiazepines may increase sedation, weakness, and drowsiness in advanced cancer patients.
Myoclonic activity can be interrupted by drugs with muscle relaxant effects. We chose dantrolene, a drug with only peripheral effects and one that is well known for treating muscle rigidity. It has antispasmotic properties with a specific inhibitory mechanism on the Ca2+ release at the level of the sarcoplasmatic reticulum of the striated muscle. Reduction of post-contraction involuntary, myoelectrical activity and muscle spasm have been reported after dantrolene treatment . A direct depressive effect on the muscles occurs, blocking the muscle excitation-contraction coupling. Therefore the drug does not produce muscular block, but depresses the mechanical response [18,19]. In this study, the muscle contraction activity responded at doses of 50-100 mg a day, a dose chosen based on our previous experience with chronic pain.
Muscle spasm is difficult to assess in term of intensity, frequency, or duration, and the evaluation was done directly by the patient, who showed an improvement in his quality of life for the residual survival time, in spite of advancing disease. No important side effects were observed. In the second patient, a single dose was chosen for the prevalence of the symptom during the night.
Dantrolene may be a promising alternative for treating muscular disorders associated with opioid therapy. However, other studies should be performed to establish the mechanism of opioid-induced myoclonus and to confirm this observation.
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