This study examines the potential efficacy of acetyl-L-carnitine (ALC) to prevent and treat paclitaxel-induced pain. Rats received four intraperitoneal (i.p.) injections of 2 mg/kg paclitaxel on alternate days which, following a short delay induced marked mechanical hypersensitivity. Daily administration of ALC (50 mg/kg and 100 mg/kg; p.o.; concurrently with paclitaxel and for 14 days afterwards) prevented the development of paclitaxel-induced pain. This effect was long lasting, for at least 3 weeks after the last dose of ALC. In a separate experiment, daily administration of ALC (100 mg/kg; p.o.; for 10 days) to rats with established paclitaxel-induced pain produced an analgesic effect. This effect dissipated shortly after ALC treatment was withdrawn. We conclude that ALC may be useful in the prevention and treatment of chemotherapy-induced painful peripheral neuropathy.

PURPOSE:This randomized phase II study was conducted to investigate the efficacy of cryotherapy in preventing peripheral neuropathy and dermatological adverse events in breast cancer patients treated with weekly paclitaxel.

METHODS:Patients treated with 12 weekly doses of paclitaxel for breast cancer were randomized (1:1) into a cryotherapy or control group. The primary endpoint was the percentage of patients with a marked decrease in the Functional Assessment of Cancer Therapy-Neurotoxicity (FACT-NTX) score. The secondary endpoints were Patient Neurotoxicity Questionnaire (PNQ), Common Terminology Criteria for Adverse Event (CTCAE) for peripheral neuropathy, and FACT-Taxane score.

RESULTS:Forty-four patients were randomly assigned to the cryotherapy (n = 22) or control groups (n = 22). The percentage of patients with a marked decrease in FACT-NTX scores was significantly lower in the cryotherapy group than in the control group (41 vs. 73%, p = 0.03). The incidence of CTCAE grade ≥ 2 sensory (p = 0.001) and motor peripheral neuropathy (p = 0.01), and PNQ grade D or higher for sensory peripheral neuropathy (p = 0.02), and decrease in the FACT-Taxane score (p = 0.02) were also significantly lower in the cryotherapy group than in the control group. There were no serious side effects associated with cryotherapy.

CONCLUSION:Cryotherapy is an effective approach for prevention of peripheral neuropathy and dermatological adverse events in breast cancer patients treated with weekly paclitaxel.

Prophylactic treatment with acetyl-L-carnitine (ALCAR) prevents the neuropathic pain syndrome that is evoked by the chemotherapeutic agent, paclitaxel. The paclitaxel-evoked pain syndrome is associated with degeneration of the intraepidermal terminal arbors of primary afferent neurons, with the activation of cutaneous Langerhans cells, and with an increased incidence of swollen and vacuolated axonal mitochondria in A-fibers and C-fibers. Previous work suggests that ALCAR is neuroprotective in other nerve injury models and that it improves mitochondrial dysfunction. Thus, we examined whether the prophylactic efficacy of ALCAR was associated with the prevention of intraepidermal terminal arbor degeneration, the inhibition of Langerhans cell activation, or the inhibition of swelling and vacuolation of axonal mitochondria. In animals with a confirmed ALCAR effect, we found no evidence of a neuroprotective effect on the paclitaxel-evoked degeneration of sensory terminal arbors or an inhibition of the paclitaxel-evoked activation of Langerhans cells. However, ALCAR treatment completely prevented the paclitaxel-evoked increase in the incidence of swollen and vacuolated C-fiber mitochondria, while having no effect on the paclitaxel-evoked changes in A-fiber mitochondria. Our results suggest that the efficacy of prophylactic ALCAR treatment against the paclitaxel-evoked pain may be related to a protective effect on C-fiber mitochondria.

PURPOSE:This pilot trial aimed to assess if cooling hands and feet with crushed ice during receipt of paclitaxel helps prevent peripheral neuropathy.

METHODS:This prospective, randomized trial compared cryotherapy to standard care in patients initiating paclitaxel weekly x 12. For those on cryotherapy, hands and feet were cooled starting 15 min prior to and ending 15 min after each paclitaxel dose. EORTC QLQ-CIPN20 was completed at baseline, weekly x12, then monthly x6. Area under the curve (AUC) was calculated for subscale scores, adjusting for baseline, and compared between arms (Wilcoxon rank-sum test). Cross-study comparisonsused data from 2 prior similarly-conducted neuropathy trials.

RESULTS:Forty-six patients were accrued. Three withdrew and one was ineligible. Of the remaining 42 (21 cryotherapy, 21 control), 39 (19 cryotherapy, 20 control) were analyzable for AUC. Cryotherapy was well tolerated, but the AUC of the CIPN20 sensory scores over 12 weeks of paclitaxel was not found to differ between the study arms (mean difference 3.45, 95% CI -3.13 to 10.02, p = 0.26). However, the control arm of the current trial experienced less neuropathy than did the placebo arms of two previous similar trials. When our cryotherapy arm was compared to the combined control arms from all three trials, the cryotherapy arm had less neuropathy (Wilcoxon Rank-Sum p = 0.01).

CONCLUSION:While there was no difference in CIPN20 scores identified between the 2 study arms in the current phase II trial, further investigation is needed given that the control arm experienced less neuropathy than was expected.

Paclitaxel, a chemotherapy drug for solid tumors, induces peripheral painful neuropathy. Bee venom acupuncture (BVA) has been reported to have potent analgesic effects, which are known to be mediated by activation of spinalα-adrenergic receptor. Here, we investigated the effect of BVA on mechanical hyperalgesia and spinal neuronal hyperexcitation induced by paclitaxel. The role of spinal α-adrenergic receptor subtypes in the analgesic effect of BVA was also observed. Administration of paclitaxel (total 8 mg/kg, intraperitoneal) on four alternate days (days 0, 2, 4, and 6) induced significant mechanical hyperalgesic signs, measured using a von Frey filament. BVA (1 mg/kg, ST36) relieved this mechanical hyperalgesia for at least two hours, and suppressed the hyperexcitation in spinal wide dynamic range neurons evoked by press or pinch stimulation. Both melittin (0.5 mg/kg, ST36) and phospholipase A2 (0.12 mg/kg, ST36) were shown to play an important part in this analgesic effect of the BVA, as they significantly attenuated the pain. Intrathecal pretreatment with the α₂-adrenergic receptor antagonist (idazoxan, 50 µg), but not α₁-adrenergic receptor antagonist (prazosin, 30 µg), blocked the analgesic effect of BVA. These results suggest that BVA has potent suppressive effects against paclitaxel-induced neuropathic pain, which were mediated by spinal α₂-adrenergic receptor.