Peripheral neuropathy is nerve conduction disruption that occurs outside of the central nervous system. It usually presents with sensory derangements, the most debilitating of which is pain in the extremities. Conventional therapies have limited success in preventing or reversing symptoms of neuropathic pain and numbness. In the past decade there has been a surge in publications suggesting acetyl-L-carnitine (ALC) may be an effective neuroprotectant and antinociceptive for peripheral neuropathy. This review highlights the uses, doses, and proposed mechanisms of action for the therapeutic effects of ALC in patients with peripheral neuropathy.
Peripheral neuropathy (PN) can be a debilitating condition, and the cause is not always understood. Presenting symptoms often are sensory derangements, including numbness (paresthesia), hypersensitivity to mild painful stimuli (hyperesthesia), pain on light touch (allodynia), electric shock sensations (dysesthesias), and spontaneous pain without stimulus.1 In more severe peripheral neuropathy, motor function impairments may present with lack of coordination, weakness, or paralysis. The autonomic nervous system may also be involved in peripheral neuropathies, and when affected, end organ function can be impaired. The causes of PN are diverse and are generally deduced through knowledge of the patient’s medical history. Some of the most common causes include diabetes, alcoholism, nutrient deficiencies (eg, vitamin B12, vitamin E, vitamin B6), exposure to toxic substances such as solvents or toxic metals (e.g., lead, arsenic), autoimmune conditions, infections (e.g., Lyme disease, syphilis), and PN secondary to drug use (e.g., chemotherapeutics, antiretroviral drugs).2 Of these, diabetic, drug-induced, and compressioninduced PN will be reviewed more closely in this paper.
The treatment of PN presents a challenge to the clinician. Opiods, anticonvulsants, antidepressants, nonsteroidal antiinflammatory drugs, and topical agents have been used with only limited success in mitigating symptoms.3,4 There is a great need for effective agents to prevent and treat PN, as the prevalence of the disease increases significantly with age. In one study, 26% of people over 65 and 54% of people over 85 had sensory
signs or symptoms of the disease.5
Acetyl-L-carnitine (ALC), a naturally occurring amino acid, may be an ideal therapeutic agent to address this otherwise recalcitrant condition. ALC is potentially effective at preventing peripheral neuropathy as well as lessening neuropathic symptoms once they have developed. Both animal and human data consistently demonstrate the neuroprotective and antinociceptive effects of ALC. In addition, ALC is well tolerated without significant risk of side effects or drug-nutrient interactions. ALC is the ester acetylated form of carnitine, a well characterized amino acid involved in fatty acid beta-oxidation in mitochondria. The final step in the synthesis of ALC takes place in the mitochondrial matrix by the enzyme acetyl-L-transferase, which uses the substrates carnitine and acetyl CoA. ALC’s normal physiological roles in the mitochondria include aiding in the export of acetyl moieties (through acetylation of various compounds) and ensuring the availability of acetyl-CoA through reversal of the enzymatic synthesis reaction.6 As an integral compound in mitochondrial function, ALC is widely distributed throughout tissues, with the highest concentrations in cardiac and skeletal muscle. The brain also has high levels, and ALC has been shown to influence neurotransmitters (NTs), including acetylcholine and dopamine.7,8,9 ALC may also prevent neural degeneration related to aging in the brain through the preservation of the neurotrophin, nerve growth factor (NGF).10,11 These actions of ALC have been known for decades and account for the popular use of ALC as an antiaging or memory-supportive nutrient.
In the early 1990s this influence on NTs was proposed as the mechanism of ALC’s antinociceptive effects. While ALC may influence pain perception through NT modulation, it is now thought that ALC’s antinociceptive effects involve direct actions at the ganglia root or peripheral axonal synapses. In addition to reducing the perception of pain, there is also evidence suggesting that ALC acts as a neuroprotectant and neuroregenerative agent. This dual action of both blocking pain perception and protecting the nerve from further damage suggests ALC is an ideal candidate to include in the treatment of peripheral neuropathy.
Drug Induced Peripheral Neuropathy
The most well established drugs causing neuropathy are antineoplastic agents. Chemotherapy induced peripheral neuropathy (CIPN) is common in patients receiving taxane-derived drugs (paclitaxel/ docetaxel), platinum compounds (cisplatin/carboplatin/oxaliplatin), vinca alkaloids (vincristine/vinblastine), thalidomide, or bortezimib. The incidence of CIPN with each agent is influenced by concomitant conditions, prior chemotherapy treatments, nutritional status, dose and duration of chemotherapy treatments, and the use of multiple antineoplastics in combination. The development of CIPN can cause dose reduction of the chemotherapy, delay of treatment, or the discontinuance of the antineoplastic altogether. Any of these disruptions of treatment can potentially lessen the efficacy of the chemotherapy regime. Further, permanent nerve damage can be found in as many as 15% of patients receiving the common combination of a platinum and taxane compounds.12 Prevention of neuropathy is an opportunity to affect the patient’s current and future quality of life, and perhaps indirectly influence survival by allowing for optimal conventional treatment.
There are many proposed patho-physiological mechanisms of CIPN for each class of chemotherapeutic agent, although no definitive mechanisms are widely agreed upon. For example, taxanes and vinca alkaloids do not lead to direct peripheral axonal degeneration, as is seen in diabetic PN. However, there is evidence showing degeneration of primary afferent nociceptive nerves at the terminal arbors within the epidermis. This causes a spontaneous discharge of these nociceptive fibers (A and C fibers), leading to the perception of pain. In a rat model of neurotoxicity, the spontaneous discharge induced by administration of paclitaxel and vincristine was diminished by 50% when ALC was given orally.13 Therefore, the protective effect of ALC on neuropathic pain development may be at least in part due to the attenuation of pain fiber discharge. A rodent study supporting this hypothesis showed that the reduction of pain fiber discharge is specifically due to ALC’s preservation of C-fiber mitochondria.14 The preservation of mitochondrial function is in keeping with the normal physiological role of ALC throughout tissues.
In contrast to taxanes, platinum compounds appear to cause damage to sensory neurons in the dorsal root ganglia. Among the proposed mechanisms of this toxicity is the reduction of circulating levels of nerve growth factor (NGF), a reparative neurotrophin.15 ALC has been shown to preserve levels of several neurotrophin compounds, including NGF, which can be hypothesized to contribute to the neuroprotective effects with platinum compounds.16
Several rodent studies have suggested the therapeutic benefit of ALC in chemotherapy induced neuropathic pain. In one study, rats were given 50 mg/kg to 100 mg/kg of ALC orally concurrent with paclitaxel administration, and for 14 days after receiving the drug. Those given ALC had significantly inhibited mechanical hypersensitivity and behavioral changes compared with those given just the vehicle solution. Protection from hypersensitivity appears to be long-lived, as the rats maintained their lack of mechanical hypersensitivity even 3 weeks after the last dose of ALC, at which point the experiment was terminated. In this same publication, ALC was given orally (100 mg/kg) to rats with established neuropathic symptoms induced by paclitaxel. While ALC was able to lessen established hypersensitivity, this effect was short-lived and symptoms of neuropathic pain developed when the ALC was discontinued.17
Pisano and colleagues showed in a rodent model that cotreatment with ALC (100 mg/kg orally) significantly diminishes the neurotoxic effects of both cisplatin and paclitaxel. This group also demonstrated there was no interference with the cytotoxic effects of paclitaxel or cisplatin when ALC was added to the medium of in vitro human cell line cancers.18 The lack of interference with the cytotoxic effects of paclitaxel and carboplatin was also demonstrated in vitro on human ovarian cancer cell lines. The presence of ALC in the growth medium did not alter the cytotoxicity of these chemotherapies, nor did it affect proliferation.19
Twenty-seven patients with CIPN induced by cisplatin (n=5), paclitaxel (n=11), or a combination of these 2 drugs
(n=11) were enrolled in a pilot trial using intravenous (IV) ALC. CIPN was diagnosed using World Health Organization (WHO) rating scale for neuropathy. Patients underwent IV infusion with 1 gram ALC over 1–2 hours for at least 10 days (range, 10–20 days). Of the 26 evaluable patients, 73% had at least 1 grade improvement on the WHO peripheral neuropathy scale. One case of insomnia was reported, but otherwise the treatment was well tolerated by all participants.20
Twenty-five patients with established CIPN (20 taxaneinduced, 5 platinum-induced) were enrolled in a phase II trial of ALC, 1 gram 3 times daily for 8 weeks. Participants in this study had ≥ grade 3 neuropathy (according to NCI-CTC criteria, 1998) and were still receiving treatment with a neurotoxic chemo, or they had ≥ grade 2 neuropathy for at least 3 months after discontinuing treatment with either drug. Of the 25 participants, 7 were still receiving neurotoxic chemotherapy during the study (6=paclitaxel, 1=vinorelbine), and 18 had residual CIPN of varying duration (3–35 months). Patients with pre-existing peripheral neuropathy or diabetes mellitus were excluded. The use of analgesics was not allowed during the study. Evaluation of neuropathy was done using a Total Neuropathy Score (TNS), which assesses subjective sensory and motor symptoms as well as objective electrophysiological measurements of nerve conduction. TNS improved significantly at 8 weeks in 23 out of
25 patients (P=0.0003). The only patient in the trial to have a significantly worsening TNS was the patient receiving vinorelbine. Symptomatic relief was also reported in all but the patient receiving vinorelbine. Amelioration of symptoms was independent of the type of chemotherapy that induced the neuropathy, or the duration of CIPN post-treatment. 21
Human immunodeficiency virus (HIV)–associated peripheral neuropathy is commonly caused by nucleoside reverse transcriptase inhibitor drugs used in treatment. Antiretroviral toxic neuropathy (ATN) results from disruption of mitochondrial DNA synthesis in neurons. Perhaps exacerbating this neurotoxicity is the presence of ALC deficiency, which has been demonstrated in patients with HIV.22 Clinical trials using ALC in patients with ATN have consistently shown benefit in the majority of participants, whether using subjective or objectives measures for assessment.
In 1997, Scarpini and colleagues conducted 1 of the first studies demonstrating the potential benefit of ALC in HIV-associated polyneuropathy. Sixteen patients with HIV-associated painful PN received 0.5 or 1.0 grams of ALC either IV or intramuscularly (IM) daily for 3 weeks. Ten patients (62.5%) reported improved symptoms, 5 patients (31.25%) reported no change, and 1 patient had a worsening of symptoms.23
In 2004, a study of 21 HIV patients with established ATN assessed the effects of oral ALC (1,500 mg orally, twice daily) using skin biopsies as well as a symptom questionnaire. Biopsy samples were taken at baseline, and every 6 months and 12 months thereafter. HIV-negative, non-neuropathic controls also underwent skin biopsies at the same regular intervals. Biopsies included 5 nerve fiber types in the epidermis, dermis, and sweat glands, quantified by histoimmunochemical staining. At 6 months there was an increase in all fiber types, with a significant increase in the number of sensory fibers in the dermis (P<0.05) and epidermis (P=0.006). At 24 months, increases of innervation improved in the epidermis and dermis and stabilized in the sweat glands. Neuropathic pain improved in 76% of patients receiving ALC and was unchanged in 19%.24 The increase in nerve fibers suggests the analgesic effect of ALC may ultimately be due to nerve regeneration. Further, continuing improvements in the quantity of nerve endings found in the skin as far as 24 months from baseline imply that long-term use of ALC may be needed for maximal nerve regeneration.
In an open-label trial of 20 patients with painful ATN, ALC (2,000 mg/day orally) was given for 4 weeks. Assessment of symptoms was done using the short-form McGill Pain Questionnaire weekly throughout the study. An 11-point intensity scale based on this questionnaire was used to render a pain intensity score. Participants also underwent electromyography at baseline and the study’s conclusion. After 4 weeks, the pain intensity score decreased significantly, from 7.35 +/- 1.98 (mean +/- SD) at baseline to 5.80 +/- 2.63 (P=0.0001). While subjective symptoms improved, electromyography scores did not change in this 4-week study.25
In a double-blind, placebo-controlled trial of 90 patients with ATN, neuropathy was assessed using several standard questionnaires of symptomatology, including the visual analog scale (VAS) and McGill Pain Questionaire. For the initial 14 days, patients were randomized to receive either ALC, 500 mg IM twice daily (n=43) or an IM injection of a placebo (n=47). All participants then went on to an open label phase of oral ALC, 1,000 mg twice daily for 42 days. After the IM injections for 14 days, only the group receiving ALC had significant pain reduction (P=0.022). At the conclusion of the study, there was a reduction in symptomatology across both groups. Both the intramuscular and oral routes had good tolerability with no adverse effects reported.26
In an open-label, single-arm pilot trial of 21 patients with ATN, intraepidermal nerve fiber density and mitochondrial DNA were assessed via skin biopsy. All study participants received ALC (3,000 mg/day orally). While the objective measures of nerve fiber density and mitochondrial DNA did not differ from baseline, subjective symptoms of pain, paresthesis, and numbness were all significantly lessened (P<0.01 for all parameters).27
Diabetic Peripheral Neuropathy
Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes. The classic presentation is numbness in the toes and/or fingers bilaterally, which progresses in a “stocking pattern” up the limb. Of clinical relevance, peripheral neuropathy can be asymptomatic in this patient population. Further, there may be a trend in diabetic patients toward ALC deficiency, which would contribute to neuronal degeneration.28 The prevalence of DPN is estimated to be 43% for all diabetics, with a higher prevalence in type 2 diabetes (50.8%) versus type I (25.1%).29
While the molecular mechanisms of DPN vary between type 1 and type 2 diabetes, they both result in axonal degeneration, which is prevented with ALC.30 This has been demonstrated in diabetic rat models, where axonal degeneration is associated with reduced nerve conduction velocity. Many rodent studies have shown that ALC prevents the diabetic-induced disruption in nerve transmission specifically.31,32,33, 34
There are also clinical data corroborating ALC’s role as a neuroprotectant in DN. In a double-blind, multicenter trial of 333 patients with established DPN, ALC significantly reduced both objective and subjective measures of neuropathy. Intervention consisted of 10 days of intramuscular injections (1,000 mg/day) of ALC, followed by a daily oral administration of 2,000 mg ALC for 12 months. Measurements of nerve conduction velocity (NCV) and amplitude were established at baseline. 294 of the participants had measurably impaired NCV and amplitude. At 12 months, there was a statistically significant improvement in average NCV in the intervention group versus the placebo group (P=0.01). Pain perception was also assessed using a visual analogue scale (VAS). After 12 months, mean VAS scores of the intervention group were 49% lower than their baseline average, while the placebo group had a reduction of only 8% (P=0.01). The authors concluded that ALC may be a “promising treatment option for patients with diabetic neuropathy.”35
An analysis of 2 randomized, placebo-controlled multicenter prospective studies of type 1 and type 2 diabetic patients with DPN (San Antonio criteria) was undertaken using frozen data points. The 2 studies that were pooled for analysis included 1 study across 28 centers in the United States and Canada (U.S.-Canada Study [UCS]) and 34 U.S., Canadian, and European centers (UCES). A total of 1,257 participants were considered in the analysis. ALC orally (500 mg or 1,000 mg 3 times per day) or placebo was used in both the UCS and the UCES studies. Overall compliance by study participants is not stated and is presumed to be less than complete given the yearlong duration of the data. End points of nerve conduction velocity, vibration perception, and a VAS for pain were used to assess neuropathic signs/symptoms. In addition, at baseline and at the study’s conclusion, 245 participants underwent nerve fiber biopsy. While nerve conduction velocities and amplitudes did not improve, there was improvement in vibration perception and pain in the cohort taking 1,000 mg 3 times per day. Nerve fiber numbers and regenerating nerve fiber clusters were significantly improved in the group receiving 500 mg ALC 3 times per day (P=0.049 and P=0.033, respectively). In the arm that was taking 1,000 mg ALC 3 times per day, there was a trend toward nerve improvement, but it was not statistically significant. Of note in this analysis, ALC alleviated neuropathic pain most effectively in patients with type 2 diabetes, and this effect was inversely correlated with the duration of DPN.36
In addition to the antinociceptive effects of ALC in sensory neuropathies, there may be a therapeutic benefit to the autonomic nerves as well. In a rodent study using steptozocin-induced diabetic rats, both sympathetic and parasympathetic cardiac tone was intentionally reduced in the rodents. ALC was able to reverse both bradycardia and rhythm disturbance compared to placebo.31 This is in keeping with earlier animal studies that suggested the protective effects of ALC on autonomic nerve damage involving the gastrointestinal tract.37
Compression-Induced Peripheral Neuropathy
Compression induced PN is the result of any physical impingement of nerve fibers. In a randomized, double-blind study, hospitalized patients with established diagnoses of moderate sciatica were recruited to receive either ALC (1,180 mg/ day) or alpha-lipoic acid (600 mg/day). Both questionnaires and electromyography were used to assess the patients at baseline and at 60 days. There was a statistically significant improvement in subjective symptoms at day 60 versus baseline for both groups. Electromyopathy also showed significant improvement in both groups at day 60. Of note, in this study, alpha-lipoic acid appeared to have a greater effect than ALC on sciatic pain.38
ALC may act as a neuroprotectant by inhibiting the apoptotic pathways within nerves. In an accepted rat model of PN, the sciatic nerve undergoes loose ligation, a chronic constriction injury. Using this model, it was demonstrated that treatment of animals with ALC, but not with gabapentin or carnitine, was able to thwart apoptosis of the nerve cells and limit damage to the sciatic nerve.39 This group also demonstrated an increase in cytochrome C release, activation of caspase 3, and resultant fragmentation of the genome in nerves undergoing loose ligation. ALC was able to abrogate these parameters, implying that ALC may act to spare neurons through an antiapoptotic mechanism.
In another rodent study, the sciatic nerve underwent compression for 30 days to simulate compression-induced neuropathy. Three control groups were used; group 1 had the right sciatic nerve severed at the start of the experiment and the soleus muscle removed, group 2 underwent compression for 30 days only, and group 3 was composed of rats that underwent sciatic compression for 30 days followed by 30 days of decompression. Two remaining groups received ALC (20 mg/kg/day intraperitoneal) on days 30–60. In group 4 this was accompanied by decompression of the nerve, while group 5 received ALC without decompression. Analysis included the histopathophysiologic features of the sciatic nerve and the weight of soleus muscle at time of sacrifice. Not surprisingly, decompression significantly improved the recovery of nerves. The addition of ALC in decompressed nerves also enhanced the clinical and histopathological recovery of the nerves that were decompressed but had no effect on nerves with continued compression.40
Acetyl-L-carnitine (ALC) is a naturally occurring amino acid derivative that has both neuroprotective and antinociceptive effects. The mechanisms of action of ALC are not clear and are likely to be multifactorial, with effects on circulating neurotrophins, mitochondrial function (including anti-apoptotic effects), and synaptic transmission influencing both nerve structure/ function and patient perception of neuropathic symptoms. Clinical trials of several prominent causes of peripheral neuropathy suggest oral doses from 1,000 mg daily to 3,000 mg daily are effective for symptom relief in a majority of patients. Electrophysiological testing and skin biopsies substantiate the regenerative capacity of ALC on nerve innervation. Some studies suggest that the regenerative capacity of ALC continues for up to 24 months after beginning therapy. Tolerance to ALC appears to be excellent with mild, infrequent side effects, including insomnia and gastric irritation. Given the level of evidence of ALC’s therapeutic effects on various types of PN combined with its lack of toxicity, ALC has the potential to dramatically affect the quality of life of patients with PN.
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