Ambroxol for neuropathic pain: hiding in plain sight?

ABSTRACT: Ambroxol is a multifaceted drug with primarily mucoactive and secretolytic actions, along with anti-inflammatory, antioxidant, and local anaesthetic properties. It has a long history of use in the treatment of respiratory tract diseases and has shown to be efficacious in relieving sore throat. In more recent years, ambroxol has gained interest for its potential usefulness in treating neuropathic pain. Research into this area has been slow, despite clear preclinical evidence to support its primary analgesic mechanism of action-blockade of voltage-gated sodium (Na v ) channels in sensory neurons. Ambroxol is a commercially available inhibitor of Na v 1.8, a crucial player in the pathophysiology of neuropathic pain, and Na v 1.7, a particularly exciting target for the treatment of chronic pain. In this review, we discuss the analgesic mechanisms of action of ambroxol, as well as proposed synergistic properties, followed by the preclinical and clinical results of its use in the treatment of persistent pain and neuropathic pain symptoms, including trigeminal neuralgia, fibromyalgia, and complex regional pain syndrome. With its well-established safety profile, extensive preclinical and clinical drug data, and early evidence of clinical effectiveness, ambroxol is an old drug worthy of further investigation for repurposing. As a patent-expired drug, a push is needed to progress the drug to clinical trials for neuropathic pain. We encourage the pharmaceutical industry to look at patented drug formulations and take an active role in bringing an optimized version for neuropathic pain to market.

[Tapentadol versus classical WHO-III opioids for chronic back pain. Health services research study based on representative data from health insurance funds]. / Tapentadol versus klassische WHO-III-Opioide bei chronischen Rückenschmerzen : Versorgungsforschungsstudie auf Basis repräsentativer Krankenkassendaten.

BACKGROUND/OBJECTIVE: In clinical trials, tapentadol prolonged release (PR) showed a more favourable gastrointestinal tolerability profile compared to other strong opioids in the treatment of pain. The present analysis compared tapentadol PR and classical WHO-III PR opioids in routine clinical practice. METHOD: Retrospective cohort study (matched pair approach) using anonymised health insurance data of patients with chronic low back pain who were prescribed strong opioids following pretreatment with WHO-I/II analgesics. Data were analysed from the date of first prescription in 2015 over a maximum period of two years. The primary analysis parameter was the prescription of laxatives. RESULTS: Data of 227 patients per cohort could be included in the analysis. Significantly fewer tapentadol PR than WHO-III PR patients were prescribed laxatives (20.3% vs. 37%; p < 0.0001). In addition, laxative dosages were significantly lower in the tapentadol PR cohort (26.4 vs. 82.5 defined daily doses; p < 0.0001). A significant difference in laxative prescription was also observed under long-term treatment (tapentadol PR patients 27.7% vs. WHO-III PR patients 50%; p = 0.0029). CONCLUSION: Routine clinical practice indirectly confirmed the more favourable gastrointestinal tolerability of tapentadol PR in the treatment of chronic pain which had previously been demonstrated in clinical trials and non-interventional studies.

Cartilage degeneration post-meniscectomy performed for degenerative disease versus trauma: data from the Osteoarthritis Initiative.

OBJECTIVE: To compare the extent of cartilage deterioration in knees with prior meniscal resection related to trauma versus knees with resection related to degenerative disease, and to compare cartilage deterioration in knees with meniscal surgery to knees without meniscal surgery, controlling for prior knee trauma. MATERIALS AND METHODS: In this cross-sectional study, we assessed cartilage deterioration in right knees of Osteoarthritis Initiative participants: (i) with meniscal surgery due to injury (n = 79); (ii) matched control knees with a prior injury but without meniscal surgery (n = 79); (iii) with meniscal surgery but without preceding injury (n = 36); and (iv) matched control knees without meniscal surgery or prior knee injury (n = 36). Cartilage composition was measured using T2 measurements derived using semi-automatic cartilage segmentation of the right. Linear regression analysis was used to compare compartmental values of T2 between groups. RESULTS: Comparing the mean T2 values in surgical cases with and without injury our results did not show significant differences (group i vs. iii, p > 0.05). However, knees with previous meniscal surgery showed significantly (p < 0.001) higher mean T2 values across all compartments (i.e., global T2) when compared to those without meniscal surgery for both knees with a history of trauma (group i vs. ii) and knees without prior trauma (group iii vs. iv). Similar results were obtained when analyzing the compartments separately. CONCLUSIONS: Cartilage deterioration, assessed by T2, is similar in knees undergoing meniscal surgery after trauma and for degenerative conditions. Both groups demonstrated greater cartilage deterioration than nonsurgical knees, controlling for prior knee injury.

Ambroxol for the treatment of fibromyalgia: science or fiction?

Fibromyalgia appears to present in subgroups with regard to biological pain induction, with primarily inflammatory, neuropathic/neurodegenerative, sympathetic, oxidative, nitrosative, or muscular factors and/or central sensitization. Recent research has also discussed glial activation or interrupted dopaminergic neurotransmission, as well as increased skin mast cells and mitochondrial dysfunction. Therapy is difficult, and the treatment options used so far mostly just have the potential to address only one of these aspects. As ambroxol addresses all of them in a single substance and furthermore also reduces visceral hypersensitivity, in fibromyalgia existing as irritable bowel syndrome or chronic bladder pain, it should be systematically investigated for this purpose. Encouraged by first clinical observations of two working groups using topical or oral ambroxol for fibromyalgia treatments, the present paper outlines the scientific argument for this approach by looking at each of the aforementioned aspects of this complex disease and summarizes putative modes of action of ambroxol. Nevertheless, at this point the evidence basis for ambroxol is not strong enough for clinical recommendation.

[Tapentadol prolonged release improves analgesia, functional impairment and quality of life in patients with chronic pain who have previously received oxycodone/naloxone]. / Verbesserte Analgesie, Funktionalität und Lebensqualität unter Tapentadol retard.

STUDY OBJECTIVE: This subgroup analysis of a prospective, non-interventional study involving general practitioners and internists investigated the administration of tapentadol prolonged release (tapentadol PR; Palexia retard) for the treatment of patients who have previously received oxycodone/naloxone. METHODS: From the overall effectiveness sample (n = 5,002) data of all patients who were previously treated with oxycodone/naloxone in a fixed combination (n = 382) were included in this analysis. Data collection during the 3-month observation period included previous and concomitant analgesic treatment, tapentadol PR dosage, pain intensity, functional impairment, and tolerability of tapentadol PR. Health related quality of life was documented at baseline and at the end of observation by patients using the SF-12 questionnaire. RESULTS: Back pain was the most common cause of pain. Including all pain diagnoses, mixed type of pain (nociceptive and neuropathic) predominated. The oxycodone/naloxone pretreatment was multifold combined with strong opioids (10.2%), weak opioids (29.3%), non- opioids (78.3%), co-analgesics (56.0%) and analgesic rescue medication (26.9%). Switching to tapentadol PR resulted in a mean pain reduction of 3.41 points from 7.29 ± 1.40 at baseline to 3.88 ± 1.86 at end of observation (NRS 11, 11-point pain scale; descriptive p value ≤ 0.001; n = 373), using a final average daily dosage of 252.9 mg tapentadol PR. In all four categories assessing the pain-related functional impairment, significant improvements have been achieved. In addition to significantly reduced pain-related impairments of everyday activities patients' data documented significant improvements in physical and mental SF-12 total scores, which initially were already at critically low range. A good tolerability of tapentadol PR therapy was reported. CONCLUSIONS: Patients, who were previously treated with oxycodone/naloxone, benefit from a tapentadol PR therapy as well: data analysis shows a clinically relevant improvement of analgesia, functionality and quality of life. Furthermore, the previous analgesic "co"-medication could be reduced during tapentadol PR therapy.

Can treatment success with 5% lidocaine medicated plaster be predicted in cancer pain with neuropathic components or trigeminal neuropathic pain?

An expert group of 40 pain specialists from 16 countries performed a first assessment of the value of predictors for treatment success with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain. Results were based on the retrospective analysis of 68 case reports (sent in by participants in the 4 weeks prior to the conference) and the practical experience of the experts. Lidocaine plaster treatment was mostly successful for surgery or chemotherapy-related cancer pain with neuropathic components. A dose reduction of systemic pain treatment was observed in at least 50% of all cancer pain patients using the plaster as adjunct treatment; the presence of allodynia, hyperalgesia or pain quality provided a potential but not definitively clear indication of treatment success. In trigeminal neuropathic pain, continuous pain, severe allodynia, hyperalgesia, or postherpetic neuralgia or trauma as the cause of orofacial neuropathic pain were perceived as potential predictors of treatment success with lidocaine plaster. In conclusion, these findings provide a first assessment of the likelihood of treatment benefits with 5% lidocaine-medicated plaster in the management of cancer pain with neuropathic components and trigeminal neuropathic pain and support conducting large, well-designed multicenter studies.

Capsaicin 8% patch for peripheral neuropathic pain: review of treatment best practice from 'real-world' clinical experience.

SUMMARY The capsaicin 8% patch is licensed in Europe for the treatment of peripheral neuropathic pain in nondiabetic adults. In controlled trials it provided pain relief for up to 3 months with a single 30- or 60-min application. In this article, a group of pain specialists from Germany and the UK share their considerable experience of real-world use of the capsaicin 8% patch. This experience comes from treating >200 patients with a variety of neuropathic pain etiologies including postherpetic neuralgia, peripheral neuropathy and cancer-related neuropathy. These patients, a slight majority of whom were female, had experienced neuropathic pain for varied lengths of time (3 months to >15 years) and the majority were receiving concomitant medications for their pain at the time of capsaicin 8% patch treatment. Observations by the group suggest that patients with positive symptoms might respond best to therapy. To optimize response to treatment, the group reports that it is important to achieve good adhesion of the patch to the skin. The experience of the group is that the capsaicin 8% patch is a tolerable treatment and local anesthetic pretreatment may not always be required. Cooling measures used after treatments were found to be the most practical and beneficial means of relieving any treatment-related discomfort. The group observed that transient, clinically important increases in blood pressure owing to treatment-related discomfort are very rare and they have seen no correlation between treatment-related discomfort or erythema and response to treatment. In the real-life clinical setting, response to capsaicin 8% patch treatment may be higher than observed in the clinical trial program. Response to retreatment also appears to be equal to that of the first treatment, even in patients treated for the fifth time. It was also observed that patients receiving capsaicin 8% patch treatment are often able to reduce their intake of concomitant pain medications. Observations from real-life use of the capsaicin 8% patch will help to maximize its therapeutic potential.