Peter R. Kamerman

Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis.

BACKGROUND New drug treatments, clinical trials, and standards of quality for assessment of evidence justify an update of evidence-based recommendations for the pharmacological treatment of neuropathic pain. Using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE), we revised the Special Interest Group on Neuropathic Pain (NeuPSIG) recommendations for the pharmacotherapy of neuropathic pain based on the results of a systematic review and meta-analysis. METHODS Between April, 2013, and January, 2014, NeuPSIG of the International Association for the Study of Pain did a systematic review and meta-analysis of randomised, double-blind studies of oral and topical pharmacotherapy for neuropathic pain, including studies published in peer-reviewed journals since January, 1966, and unpublished trials retrieved from ClinicalTrials.gov and websites of pharmaceutical companies. We used number needed to treat (NNT) for 50% pain relief as a primary measure and assessed publication bias; NNT was calculated with the fixed-effects Mantel-Haenszel method. FINDINGS 229 studies were included in the meta-analysis. Analysis of publication bias suggested a 10% overstatement of treatment effects. Studies published in peer-reviewed journals reported greater effects than did unpublished studies (r(2) 9·3%, p=0·009). Trial outcomes were generally modest: in particular, combined NNTs were 6·4 (95% CI 5·2-8·4) for serotonin-noradrenaline reuptake inhibitors, mainly including duloxetine (nine of 14 studies); 7·7 (6·5-9·4) for pregabalin; 7·2 (5·9-9·21) for gabapentin, including gabapentin extended release and enacarbil; and 10·6 (7·4-19·0) for capsaicin high-concentration patches. NNTs were lower for tricyclic antidepressants, strong opioids, tramadol, and botulinum toxin A, and undetermined for lidocaine patches. Based on GRADE, final quality of evidence was moderate or high for all treatments apart from lidocaine patches; tolerability and safety, and values and preferences were higher for topical drugs; and cost was lower for tricyclic antidepressants and tramadol. These findings permitted a strong recommendation for use and proposal as first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin; a weak recommendation for use and proposal as second line for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only. INTERPRETATION Our results support a revision of the NeuPSIG recommendations for the pharmacotherapy of neuropathic pain. Inadequate response to drug treatments constitutes a substantial unmet need in patients with neuropathic pain. Modest efficacy, large placebo responses, heterogeneous diagnostic criteria, and poor phenotypic profiling probably account for moderate trial outcomes and should be taken into account in future studies. FUNDING NeuPSIG of the International Association for the Study of Pain.

Adaptive heterothermy and selective brain cooling in arid-zone mammals.

Adaptive heterothermy and selective brain cooling are regarded as important thermal adaptations of large arid-zone mammals. Adaptive heterothermy, a process which reduces evaporation by storing body heat, ought to be enhanced by ambient heat load and by water deficit, but most mammals studied fail to show at least one of those attributes. Selective brain cooling, the reduction of brain temperature below arterial blood temperature, is most evident in artiodactyls, which possess a carotid rete, and traditionally has been considered to protect the brain during hyperthermia. The development of miniature ambulatory data loggers for recording body temperature allows the temperatures of free-living wild mammals to be measured in their natural habitats. All the African ungulates studied so far, in their natural habitats, do not exhibit adaptive heterothermy. They have low-amplitude nychthemeral rhythms of temperature, with mean body temperature over the night exceeding that over the day. Those with carotid retes (black wildebeest, springbok, eland) employ selective brain cooling but zebra, without a rete, do not. None of the rete ungulates, however, seems to employ selective brain cooling to prevent the brain overheating during exertional hyperthermia. Rather, they use it at rest, under moderate heat load, we believe in order to switch body heat loss from evaporative to non-evaporative routes.

Neuropathic pain: an updated grading system for research and clinical practice.

Abstract The redefinition of neuropathic pain as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system,” which was suggested by the International Association for the Study of Pain (IASP) Special Interest Group on Neuropathic Pain (NeuPSIG) in 2008, has been widely accepted. In contrast, the proposed grading system of possible, probable, and definite neuropathic pain from 2008 has been used to a lesser extent. Here, we report a citation analysis of the original NeuPSIG grading paper of 2008, followed by an analysis of its use by an expert panel and recommendations for an improved grading system. As of February, 2015, 608 eligible articles in Scopus cited the paper, 414 of which cited the neuropathic pain definition. Of 220 clinical studies citing the paper, 56 had used the grading system. The percentage using the grading system increased from 5% in 2009 to 30% in 2014. Obstacles to a wider use of the grading system were identified, including (1) questions about the relative significance of confirmatory tests, (2) the role of screening tools, and (3) uncertainties about what is considered a neuroanatomically plausible pain distribution. Here, we present a revised grading system with an adjusted order, better reflecting clinical practice, improvements in the specifications, and a word of caution that even the “definite” level of neuropathic pain does not always indicate causality. In addition, we add a table illustrating the area of pain and sensory abnormalities in common neuropathic pain conditions and propose areas for further research.

HIV Neuropathy Risk Factors and Symptom Characterization in Stavudine-Exposed South Africans

CONTEXT HIV-associated sensory neuropathy (HIV-SN) is a frequent complication of both HIV and neurotoxic antiretroviral medications such as stavudine. OBJECTIVES To determine the prevalence, risk factors, and clinical characteristics of symptomatic HIV-SN in a Black South African cohort of patients exposed to stavudine. METHODS HIV-positive Black South Africans (n=395) who had received stavudine for at least six months were recruited at the Virology Clinic of the Charlotte Maxeke Academic Johannesburg Hospital, South Africa, and screened for neuropathy using the AIDS Clinical Trials Group neuropathy screening tool. HIV-SN was defined as present if the patient had both symptoms and signs of peripheral neuropathy. If present, the distribution and intensity of symptoms were recorded. In addition, anthropomorphic, demographic, and clinical information were recorded and analyzed as risk factors. RESULTS The prevalence of symptomatic HIV-SN was 57% (226 of 395). Increasing age and height were independently associated with the development of SN among patients who had used stavudine. Pain was the primary symptom reported by participants with HIV-SN (76%, 172 of 226), followed by numbness (48%, 108 of 226), and pins and needles (46%, 105 of 226). About three-quarters of participants rated their symptoms as being of moderate to severe intensity. Symptoms were always present in the feet and only 23% experienced symptoms proximal to the feet. CONCLUSION HIV-SN was common in this population and frequently associated with moderate to severe pain in the feet. HIV-SN was significantly associated with increasing age and height, factors that could be measured at no added cost prior to stavudine prescription, allowing higher risk patients to be offered priority access to nonneurotoxic drugs.

Pathogenesis of HIV‐associated sensory neuropathy: evidence from in vivo and in vitro experimental models

HIV‐associated sensory neuropathy (HIV‐SN) is a frequent neurological complication of HIV infection and its treatment with some antiretroviral drugs. We review the pathogenesis of the viral‐ and drug‐induced causes of the neuropathy, and its primary symptom, pain, based on evidence from in vivo and in vitro models of HIV‐SN. Viral coat proteins mediate nerve fibre damage and hypernociception through direct and indirect mechanisms. Direct interactions between viral proteins and nerve fibres dominate axonal pathology, while somal pathology is dominated by indirect mechanisms that occur secondary to virus‐mediated activation of glia and macrophage infiltration into the dorsal root ganglia. The treatment‐induced neuropathy and resulting hypernociception arise primarily from drug‐induced mitochondrial dysfunction, but the sequence of events initiated by the mitochondrial dysfunction that leads to the nerve fibre damage and dysfunction are still unclear. Overall, the models that have been developed to study the pathogenesis of HIV‐SN, and hypernociception associated with the neuropathy, are reasonable models and have provided useful insights into the pathogenesis of HIV‐SN. As new models are developed they may ultimately lead to identification of therapeutic targets for the prevention or treatment of this common neurological complication of HIV infection.

HIV-Associated Sensory Neuropathy: Risk Factors and Genetics

HIV-associated sensory neuropathy (HIV-SN) remains a common neurological complication of HIV infection despite the introduction of effective antiretroviral therapies. Exposure to neurotoxic antiretroviral drugs and increasing age have consistently been identified as risk factors for HIV-SN, while comorbid conditions with underlying predisposition to cause peripheral neuropathy (eg, diabetes mellitus, malnutrition, isoniazid exposure), ethnicity, and increasing height also have been implicated. Genetic association studies have identified genes affecting mitochondrial function and genes involved in the inflammatory response that modify the risk for HIV-SN among patients exposed to neurotoxic antiretrovirals. However, there is a lack of data on clinical, demographic, and genetic risk factors for HIV-SN in the modern era, with the rate of HIV-SN remaining unacceptably high despite the introduction of safer medications. Thus, more work is required to identify the principal factors that increase an individual’s risk for HIV-SN so that effective preventative or therapeutic strategies can be implemented.

A year in the thermal life of a free-ranging herd of springbok Antidorcas marsupialis

SUMMARY We used miniature data loggers implanted in the abdominal cavity to measure core body temperatures at 30 min intervals in eight (three males, five females) adult free-ranging springbok Antidorcas marsupialis in their natural habitat, over a period of 11–13 months. The animals were subjected to a nychthemeral range of air temperature that often exceeded 20°C, with an absolute minimum temperature of –6°C and a maximum of 34°C. Abdominal temperature exhibited a low amplitude (∼1.2°C) nychthemeral rhythm, with a temperature peak near sunset and a trough shortly after sunrise. The amplitude of the nychthemeral rhythm of body temperature was not correlated with the 24 h range of air temperature. Although mean 24 h body temperatures were positively correlated with corresponding air temperatures, mean daily body temperature increased, on average, by only 0.02°C per 1°C increase in air temperature, so that it was only∼ 0.3°C higher in summer than in winter. Mean monthly body temperatures were strongly positively correlated with photoperiod and, in parallel with changes in the time of sunrise, the times at which the minimum and maximum body temperatures occurred were shifted ∼1.2 h earlier in summer than in winter. Annual and daily variations in body temperature of springbok, like those of other free-living African ungulates, therefore appear to reflect an endogenous rhythm, entrained by the light:dark cycle, but largely independent of fluctuations in the environmental thermal load. Springbok exhibit remarkable homeothermy and do not employ adaptive heterothermy to survive in their natural environment.

Clinical practice guidelines for management of neuropathic pain: Expert panel recommendations for South Africa

Neuropathic pain (NeuP) is challenging to diagnose and manage, despite ongoing improved understanding of the underlying mechanisms. Many patients do not respond satisfactorily to existing treatments. There are no published guidelines for diagnosis or management of NeuP in South Africa. A multidisciplinary expert panel critically reviewed available evidence to provide consensus recommendations for diagnosis and management of NeuP in South Africa. Following accurate diagnosis of NeuP, pregabalin, gabapentin, low-dose tricyclic antidepressants (e.g. amitriptyline) and serotonin norepinephrine reuptake inhibitors (duloxetine and venlafaxine) are all recommended as first-line options for the treatment of peripheral NeuP. If the response is insufficient after 2 - 4 weeks, the recommended next step is to switch to a different class, or combine different classes of agent. Opioids should be reserved for use later in the treatment pathway, if switching drugs and combination therapy fails. For central NeuP, pregabalin or amitriptyline are recommended as first-line agents. Companion treatments (cognitive behavioural therapy and physical therapy) should be administered as part of a multidisciplinary approach. Dorsal root entry zone rhizotomy (DREZ) is not recommended to treat NeuP. Given the large population of HIV/AIDS patients in South Africa, and the paucity of positive efficacy data for its management, research in the form of randomised controlled trials in painful HIV-associated sensory neuropathy (HIV-SN) must be prioritised in this country.

Neuropathic pain phenotyping by international consensus (NeuroPPIC) for genetic studies: a NeuPSIG systematic review, Delphi survey, and expert panel recommendations.

Abstract For genetic research to contribute more fully to furthering our knowledge of neuropathic pain, we require an agreed, valid, and feasible approach to phenotyping, to allow collaboration and replication in samples of sufficient size. Results from genetic studies on neuropathic pain have been inconsistent and have met with replication difficulties, in part because of differences in phenotypes used for case ascertainment. Because there is no consensus on the nature of these phenotypes, nor on the methods of collecting them, this study aimed to provide guidelines on collecting and reporting phenotypes in cases and controls for genetic studies. Consensus was achieved through a staged approach: (1) systematic literature review to identify all neuropathic pain phenotypes used in previous genetic studies; (2) Delphi survey to identify the most useful neuropathic pain phenotypes and their validity and feasibility; and (3) meeting of experts to reach consensus on the optimal phenotype(s) to be collected from patients with neuropathic pain for genetic studies. A basic “entry level” set of phenotypes was identified for any genetic study of neuropathic pain. This set identifies cases of “possible” neuropathic pain, and controls, and includes: (1) a validated symptom-based questionnaire to determine whether any pain is likely to be neuropathic; (2) body chart or checklist to identify whether the area of pain distribution is neuroanatomically logical; and (3) details of pain history (intensity, duration, any formal diagnosis). This NeuroPPIC “entry level” set of phenotypes can be expanded by more extensive and specific measures, as determined by scientific requirements and resource availability.

Pain in ambulatory HIV‐positive South Africans

We investigated the prevalence and intensity of pain, factors associated with having pain, and analgesic medications employed in a population consisting predominantly of Black African and female human immunodeficiency virus (HIV)‐positive individuals attending outpatient clinics in a rural (n = 125; 79% female; 100% Black African) and a metropolitan (n = 396; 75% female; 94% Black African) area of South Africa. Pain intensity, interference and treatment were assessed using the Wisconsin Brief Pain Questionnaire. Seventy‐two percent of rural participants and 56% of metropolitan participants had pain at the time of the interview, and this pain was moderate to severe in intensity in 60% of rural participants and 59% of metropolitan participants. Forty‐six percent of rural participants and 61% of metropolitan participants had multiple pain sites. The most common pain sites in rural participants were the abdomen (30%), chest (26%), head (19%) and genitals (15%), while in the metropolitan cohort the head (39%), feet (33%), chest (30%) and abdomen (20%) were the most common sites. In the rural cohort, antiretroviral therapy was independently associated with reduced risk of pain, while in the metropolitan cohort increasing age was weakly, but independently associated with having pain. Pharmacological management of pain was poor, with 29% of rural participants and 55% of metropolitan participants with pain not receiving any treatment. Of those receiving treatment, no participants were receiving strong opioids, and only 3% of metropolitan participants were receiving a weak opioid. Thus, HIV‐related pain is common and is poorly treated in both the rural and metropolitan setting in South Africa.