Can Milnacipran Used for Neuropathic Pain in Patients with Advanced Cancer Cause Neuromuscular and Somatosensory Disorders?

Introduction

With the advent of chemotherapy, the overall survival rate for patients with cancer has increased. However, complications involved with chemotherapy cause damage to the peripheral nervous system. In addition, cancer patients tend to have both nociceptive and neuropathic pain. There is a general perception that neuropathic pain is less responsive than nociceptive pain to opioids,^1–3 and anticonvulsants are effectively used in many patients to relieve this type of pain ⁴ in addition to antidepressants ⁵ and ketamine. ⁶ Serotonin and norepinephrine reuptake inhibitors (SNRIs) have also been recommended for treatment of neuropathic pain due to cancer, ⁷ and have found to be effective for the treatment of multiple symptoms of fibromyalgia in a randomized, double-blinded, placebo-controlled trial. ⁸ In this case, we used milnacipran, an antidepressant, as an analgesic adjuvant because controlled-release morphine sulfate, carbamazepine, amitriptyline hydrochloride, and gabapentin did not improve the patient's symptoms. Milnacipran is one of the class of drugs that are SNRIs. It is known to have fewer side effects, including thirst and suppression of gastrointestinal motility, than conventional antidepressants.

Neurologic symptoms due to the use of milnacipran are very rare. Only seven cases of neurologic adverse effects after the use of milnacipran for the treatment of depression have been reported previously. Here we report the first case of a neurologic adverse reaction observed after the use of milnacipran as an analgesic adjuvant for neuropathic pain in patients with advanced cancer.

Case Report

A 66-year-old woman was diagnosed with cancer of the left breast 7 years ago. She had a mastectomy and left axillary lymph node dissection. The breast tumor metastasized to the skin, which was treated with radiotherapy. Three years ago, she received combination chemotherapy consisting of paclitaxel plus trastuzumab. Treatment was repeated every week for eight courses. Subsequently, she received combination chemotherapy of vinorelbine plus trastuzumab, which was repeated every week for seven courses. The assessment of chemotherapy showed partial response of tumor. She experienced some numbness and tingling in her hands and feet after paclitaxel was used. She also experienced pain in her left upper extremity due to pressure on the nerve from lymph node metastases. Controlled-release morphine sulfate (40 mg/d), carbamazepine (200 mg/d), and amitriptyline hydrochloride (10 mg/d) were used to relieve pain, but this medication was ineffective and the pain persisted. Immediate hospitalization was required during the current year because of cardiac failure and liver dysfunction. After admission, her liver dysfunction improved with the discontinuation of controlled-release morphine sulfate (40 mg/d), carbamazepine (200 mg/d), and amitriptyline hydrochloride (10 mg/d), and cardiac failure was managed with diuretics. The patient had no history of substance abuse or infectious or metabolic disease. One month after admission, gabapentin (400 mg/d) was started to relieve numbness and tingling in her hands and feet. This was not effective, and hence, the dose was gradually increased to 800 mg/d, but the symptoms did not improve. Therefore, she was given 15 mg of milnacipran after dinner. The next morning she developed stiffness of the fingers, numbness in the mandible, and the soles of her feet felt swollen. She also experienced difficulty in walking. Her body temperature was 36.5°C, heart rate 80 beats per minute, respiratory rate 20 breaths per minute, and blood pressure 110/75 mm Hg. She did not experience any psychological or physical symptoms of anxiety. She had no typical muscle rigidity and the skin of her fingers, face, and feet showed no changes in appearance. Results of a complete blood cell count and biochemistry including serum calcium and magnesium levels were within normal ranges. Her evening dose of milnacipran as well the next morning dose was not given. Her symptoms immediately improved, disappeared around noon, and did not reappear subsequently. All the patient symptoms were objectified by the treating physicians.

Discussion

It is highly probable that milnacipran caused the symptoms observed in this case, because they appeared shortly after its administration and disappeared after discontinuation. There is a possibility that the patient who discontinued the SNRI may have been hyperventilating due to anxiety. This may be triggered by the inhibition of monamino reuptake. The hyperventilation may induce symptoms such as numbness of the mandible and finger stiffness. However, the median respiratory rate was 19 breaths per minute (range, 16–20 breaths per minute; mean ± standard deviation [SD], 18.8 ± 1.3) during the 2 weeks prior to the day of these symptoms. The rate of 20 was normal for her. Moreover, she did not have psychological and physical symptoms of anxiety. Our case is not related to hyperventilation due to anxiety. Seven cases of neurologic symptoms due to milnacipran have been reported previously, but the mechanism underlying these symptoms is unknown.^9–15 In all the reported cases, milnacipran was used for the treatment of depression. Two cases were reported in which severe parkinsonism occurred after milnacipran administration for 1 week or 4 months.^9,10 One case was reported in which numbness of the hands and feet occurred when the medication was changed from paroxetine to milnacipran. ¹¹ In another four cases, serotonin syndrome occurred when the dose was increased or after milnacipran was added to other medication.^12–15 All seven cases differ from our case, because they did not show rapid development of symptoms (symptoms first appeared between 3 weeks and 4 months after administration,^9,10,14,15 a high dose of milnacipran was used (100–150 mg/d),^{10–12,14,15} and milnacipran was not used as monotherapy.^13,14 We also found a report of serotonin syndrome occurring several hours after the initial administration of low-dose venlafaxine monotherapy; this represents another type of SNRI-induced serotonin syndrome. ¹⁶ Neuroleptic malignant syndrome was also reported after venlafaxine treatment. ¹⁷

As mentioned above, SNRI-induced neurologic disorders are mainly of three types: extrapyramidal syndrome, serotonin syndrome, and neuroleptic malignant syndrome. These symptoms may be based on mechanisms similar to those by which SNRIs inhibit central dopaminergic activity and increase serotonergic activity. ¹⁸ Extrapyramidal symptoms and neuroleptic malignant syndrome mainly occur 1 or 2 weeks after administration. In general, the initial presentation of extrapyramidal symptoms includes tremor, hypokinesia, rigidity, postural instability, and a mask-like face, and neuroleptic malignant syndrome manifests as acute onset of hyperthermia, rigidity, and autonomic instability. Our case is unlikely to be related to extrapyramidal symptoms and neuroleptic malignant syndrome because of its rapid development and the nature of the patient's symptoms.

In general, serotonin syndrome frequently occurs within 24 hours after administration, which is consistent with the observation in our case. The Hunter serotonin toxicity criteria, which have good sensitivity and specificity, are used to diagnose serotonin syndrome. Diagnosis by these criteria requires presence of at least one of the following characteristic features or groups of features: Spontaneous, inducible, or ocular clonus with agitation or diaphoresis; tremor and hyperreflexia; or hypertonism and temperature above 100.4°F (38°C), and ocular or inducible clonus. ¹⁹ The most important symptoms for diagnosing serotonin syndrome are tremor, akathisia, or clonus (spontaneous, inducible, and ocular). These symptoms are described as a triad of clinical features consisting of autonomic signs, neuromuscular changes and altered mental status.^18,19 In the symptoms of our case, stiffness of the fingers and numbness of the mandible are neuromuscular disorders and the soles of her feet felt swollen is a somatosensory disorder. The hypothesis about the pharmacologic origin of these symptoms is that SNRIs inhibit the serotonin reuptake of the presynaptic serotonergic neuron, and thereby, increase concentrations of serotonin in the intrasynaptic space. Hyperstimulation of postsynaptic serotonin receptors causes a wide range of symptoms, including cognitive, autonomic, and somatic symptoms. The symptoms of our case may have been a prodrome of serotonin syndrome, and they would have met the Hunter criteria if they had developed further. We managed this case, which was getting severe, by discontinuing milnacipran on early detection of symptoms. Serotonin toxicity occurs in patients who ingest a single serotonergic agent but many cases occur in patients who have ingested drug combinations that synergistically increase synaptic serotonin. ¹⁶ However, in our case, the patient did not take other agents. This patient experienced some numbness and tingling in her hands and feet after the chemotherapy for breast cancer. It might be related to the cause of the neurologic side effects. However, there is no evidence to suggest it and the cause of the symptoms are not clear.

The analgesic effect of SNRIs will likely be exploited in the management of neuropathic pain in the future; however, clinicians should be highly aware of the early adverse reactions to these agents.