Mexiletine as an Adjuvant Analgesic for the Management of Neuropathic Cancer Pain

Cancer pain can usually be managed with standard analgesic regimens; however, neuropathic pain related to tumor infiltration of major plexi can be difficult to control. Neuropathic pain is defined as pain caused by injury to or dysfunction of the peripheral or central nervous system (¹). Mexiletine, a class 1b antiarrhythmic and orally available local anesthetic sodium channel blocker structurally similar to lidocaine, has been suggested for the treatment of chronic neuropathic pain (^2–4). Although mexiletine has been suggested in the management of neuropathic cancer pain, few data are available in the literature to support such use.

We report the use of mexiletine as an adjuvant analgesic to provide pain relief for three patients with neuropathic cancer pain secondary to lumbosacral plexus tumor infiltration. All patients continued their current opioid at a constant level during the trial of mexiletine. Mexiletine was added as an adjuvant analgesic with a starting dose of 200 mg BID, increased to 200 mg TID as required for analgesia. Twice daily visual analog scales (VAS) were completed for pain and nausea (0 = no pain to 10 = worst possible pain). The use of any additional analgesics and any side effects were recorded daily.

Case Report 1

A 49-yr-old woman with carcinoma of the uterus and pelvic invasion presented with burning pelvic pain radiating to the left lower extremity. The constant pain was rated as 8 on a VAS and was associated with numbness over the left posterior thigh and leg. The pain was only partly controlled with oral morphine 180 mg daily. A directed physical examination revealed mild tenderness to palpation over the left posterior thigh with decreased light touch sensation along the posterior thigh, calf, and ankle. There was no allodynia or dysesthesia. Motor strength was normal in both lower extremities.

The patient was started on mexiletine 200 mg orally BID. Within 3 days, her pain had diminished to a VAS score <4. The dose of mexiletine was increased to 200 mg TID, and the pain VAS score varied between 1 and 4 throughout the following 7 days (Figure 1). Occasional mild nausea requiring no treatment was reported.

Figure 1: Visual analog pain scale (VAS) ratings (0 = no pain to 10 = worst possible pain) for each patient during 9 days of mexiletine therapy.

Case Report 2

A 62-yr-old woman with metastatic adenocarcinoma of the colon developed sharp pain in the right buttock with radiation to the right lower extremity. Constant pain was rated as 8 on a VAS and was associated with mild weakness in the right lower extremity. The pain was partly controlled with oral morphine 35 mg daily. Additional symptoms were mild nausea and depression. A directed physical examination revealed decreased light touch sensation along the right calf, without allodynia or hyperalgesia. Motor examination revealed 3/5 strength in the right quadriceps muscle with normal motor strength in the left lower extremity.

The patient was started on mexiletine 200 mg orally BID, and the pain VAS score was reduced to 3 during the first week of therapy (Figure 1). The daily morphine dose was reduced to 25 mg. On Day 4, the mexiletine dose was increased to 200 mg TID, but worsening nausea dictated that the mexiletine dose be returned to 200 mg orally BID. The nausea diminished to baseline but continued throughout the period of observation. Mild depression continued unchanged throughout the 9-day period. The patient reported feeling “trembly and shaky” on occasion, but no visible tremors were reported and she continued to tolerate oral mexiletine.

Case Report 3

A 51-yr-old woman with adenocarcinoma of the lung metastatic to the sacrum developed burning pain in the right buttock with radiation to the right lower extremity. The constant pain was rated as a 6 on a VAS and was only partly controlled with hydromorphone 30 mg daily, acetaminophen (650 mg QID PRN), and amitriptyline (25 mg daily). A myelogram-computed tomography scan revealed invasion of the sacrum with compression of the right S₁ nerve root. On directed physical examination, there was decreased light touch and temperature sensation over the right S₁ nerve root distribution, and a decreased right ankle reflex.

Oral mexiletine 200 mg BID was started, and the pain decreased to a score of 3 on a VAS during the 9-day observation period. Side effects of mild nausea and depression were reported. The daily opioid and adjuvant analgesic doses remained unchanged throughout the observation period.

Discussion

Patients with cancer often suffer severe pain requiring the use of opioids and adjuvant analgesics. Of patients with cancer pain, 10%–20% will require aggressive pain therapy; thus, the search for additional analgesics and adjuvant analgesics continues (⁵). Neuropathic pain is often burning, aching, or lancinating and is often associated with sensory changes (hypoesthesia, hyperesthesia, and allodynia) in the distribution of peripheral nerves (⁶). There may also be associated motor weakness and trophic skin changes (⁷). Mexiletine, an adjuvant analgesic, may be useful in the management of this subset of patients with difficult to control neuropathic cancer pain. The exact role of other adjuvant analgesics has not been clearly defined.

Mexiletine is well absorbed orally with an oral bioavailability of 80%–90%, and it has an 8- to 12-hour period of efficacy. Most metabolism occurs in the liver. Adverse effects of mexiletine include gastrointestinal disturbances (nausea and vomiting) and neurologic side effects (tremors, dizziness, ataxia, and nystagmus). These effects are dose-related and are associated with serum mexiletine levels >2 μg/mL (⁸). Evidence suggests that mexiletine provides analgesia by blocking sodium channels at both peripheral and central sites (^9,10). The ability of mexiletine to selectively block nerves in a more depolarized state makes this drug useful for blocking pain pathways in which neural activity is increased. Sensory and motor neuronal function are unaffected by these concentrations of sodium channel blockers. The minimal effective plasma concentration of mexiletine associated with pain relief is unknown.

The use of systemically administered local anesthetics has been advocated for the relief of neuropathic cancer pain (¹¹). A parenteral infusion of a local anesthetic may be useful to selected patients who do not respond to oral mexiletine (¹²).

All three of our patients with neuropathic pain reported decreased VAS scores when mexiletine was added to their analgesic regimen. All patients continued on mexiletine until they died from cancer. Whether the decrease in pain noted in these patients was an opioid-sparing effect or whether mexiletine provided pain relief that would not otherwise be relieved by opioids requires further study and research. A randomized, controlled, prospective, blinded study is needed to assess the analgesic efficacy, dose-response curve, and side effect profile of mexiletine in the treatment of neuropathic cancer pain.