Is pain perception altered in people with depression? A systematic review and meta-analysis of experimental pain research

While clinical studies suggest depressed patients may be more vulnerable to pain, experimental research is equivocal. This meta-analysis aimed to clarify whether depression is associated with altered pain perception in response to noxious stimulation and to identify factors that might influence this association. A search of major electronic databases was conducted to identify experimental studies investigating pain response in depressed participants vs. healthy controls using established pain outcome measures. Random effects meta-analysis of standardized mean differences was conducted on data from 32 studies (N=1,317). For high-intensity noxious stimulation, overall pain tolerance was similar across depressed and control groups (Hedge's g=0.09, p=0.71, studies=10). For low-intensity stimulation, a small, but statistically significant higher mean sensory threshold (g=0.35, p=0.01, studies=9) and pain threshold (g=0.32, p=0.02, studies=25) was observed in depressed participants, suggesting diminished pain. However, considerable heterogeneity in the direction and magnitude of effects was observed, indicating a likely condition-specific impact of depression on pain. Subgroup analysis found that pain threshold/tolerance was increased in depression for exteroceptive (cutaneous) stimulation but decreased for interoceptive (ischemic) stimulation, but that substantial heterogeneity remained. Overall, results provide some support for altered pain processing in depression, but suggest this link is dependent upon modality and additional, unidentified factors

NMDA receptor antagonists and pain relief: A meta-analysis of experimental trials

OBJECTIVES: We conducted a meta-analysis of controlled trials that used experimental models of acute pain and hyperalgesia to examine the analgesic effects of N-methyl-D-aspartate receptor (NMDAR) antagonists. METHODS: Six major databases were systematically searched (to 03/2018) for studies using human evoked pain models to compare NMDAR antagonists with no-intervention controls. Pain outcome data were analyzed with random-effects meta-analysis. RESULTS: Searches identified 70 eligible trials (N=1069). Meta-analysis found that low-dose ketamine (<1 mg/kg) produced a decrease in the size of hyperalgesic area (Standardized Mean Difference=0.54, CI95[0.34, 0.74], p<.001), and a 1.2-point decrease (CI95[0.88, 1.44], p<.001) in pain ratings from 4.6 to 3.4 on a 0-10 scale (a 26% reduction). Similar analgesia was observed for acute and hyperalgesic models and was constant across the dosing range (0.03-1.00 mg/kg). Moderate-high variability in effect size was observed and mild side effects (e.g. sedation, sensory disturbance) were common. No effects of dextromethorphan were found. CONCLUSIONS: Findings provide robust evidence for analgesic and anti-hyperalgesic effects of ketamine, supporting its utility for acute and chronic pain management. However, pain relief was modest, suggesting ketamine may potentially be most useful when opioids are contraindicated, rapid analgesia is required or for pain resistant to conventional medication

Tau-mediated axonal degeneration is prevented by activation of the WldS pathway

Tauopathy is characterized by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule-associated protein tau. The neuronal changes evident in tauopathy bear striking morphological resemblance to those reported in models of Wallerian degeneration. The mechanisms underpinning Wallerian degeneration are not fully understood although it can be delayed by the expression of the slow Wallerian degeneration (WldS) protein, which has also been demonstrated to delay axonal degeneration in some models of neurodegenerative disease. Given the morphological similarities between tauopathy and Wallerian degeneration, this study investigated whether tau-mediated phenotypes can be modulated by co-expression of WldS. In a Drosophila model of tauopathy in which expression of human 0N3R tau protein leads to progressive age-dependent phenotypes, WldS was expressed with and without activation of the downstream pathway. The olfactory receptor neuron circuit OR47b was used for these studies in adults, and the larval motor neuron system was employed in larvae. Tau phenotypes studied included neurodegeneration, axonal transport, synaptic deficits and locomotor behaviour. Impact on total tau was ascertained by assessing total, phosphorylated and misfolded tau levels by immunohistochemistry. Activation of the pathway downstream of WldS completely suppressed tau-mediated degeneration. This protective effect was evident even if the pathway downstream of WldS was activated several weeks after tau-mediated degeneration had become established. Though total tau levels were not altered, the protected neurons displayed significantly reduced MC1 immunoreactivity suggestive of clearance of misfolded tau, as well as a trend for a decline in tau species phosphorylated at the AT8 and PHF1 epitopes. In contrast, WldS expression without activation of the downstream protective pathway did not rescue tau-mediated degeneration in adults or improve tau-mediated neuronal dysfunction including deficits in axonal transport, synaptic alterations and locomotor behaviour in tau-expressing larvae. This collectively implies that the pathway mediating the protective effect of WldS intersects with the mechanism(s) of degeneration initiated by tau and can effectively halt tau-mediated degeneration at both early and late stages. Understanding the mechanisms underpinning this protection could identify much-needed disease-modifying targets for tauopathies.</p

Pain perception in Parkinson’s disease: A systematic review and meta-analysis of experimental studies

While hyperalgesia (increased pain sensitivity) has been suggested to contribute to the increased prevalence of clinical pain in Parkinson’s disease (PD), experimental research is equivocal and mechanisms are poorly understood. We conducted a meta-analysis of studies comparing PD patients to healthy controls (HCs) in their response to experimental pain stimuli. Articles were acquired through systematic searches of major databases from inception until 10/2016. Twenty-six studies met inclusion criteria, comprising 1292 participants (PD = 739, HCs = 553). Random effects meta-analysis of standardized mean differences (SMD) revealed lower pain threshold (indicating hyperalgesia) in PD patients during unmedicated OFF states (SMD = 0.51) which was attenuated during dopamine-medicated ON states (SMD = 0.23), but unaffected by age, PD duration or PD severity. Analysis of 6 studies employing suprathreshold stimulation paradigms indicated greater pain in PD patients, just failing to reach significance (SMD = 0.30, p= = 0.06). These findings (a) support the existence of hyperalgesia in PD, which could contribute to the onset/intensity of clinical pain, and (b) implicate dopamine deficiency as a potential underlying mechanism, which may present opportunities for the development of novel analgesic strategies

Gabapentin for chronic pelvic pain in women (GaPP2):a multicentre, randomised, double-blind, placebo-controlled trial

BackgroundChronic pelvic pain affects 2–24% of women worldwide and evidence for medical treatments is scarce. Gabapentin is effective in treating some chronic pain conditions. We aimed to measure the efficacy and safety of gabapentin in women with chronic pelvic pain and no obvious pelvic pathology.MethodsWe performed a multicentre, randomised, double-blind, placebo-controlled randomised trial in 39 UK hospital centres. Eligible participants were women with chronic pelvic pain (with or without dysmenorrhoea or dyspareunia) of at least 3 months duration. Inclusion criteria were 18–50 years of age, use or willingness to use contraception to avoid pregnancy, and no obvious pelvic pathology at laparoscopy, which must have taken place at least 2 weeks before consent but less than 36 months previously. Participants were randomly assigned in a 1:1 ratio to receive gabapentin (titrated to a maximum dose of 2700 mg daily) or matching placebo for 16 weeks. The online randomisation system minimised allocations by presence or absence of dysmenorrhoea, psychological distress, current use of hormonal contraceptives, and hospital centre. The appearance, route, and administration of the assigned intervention were identical in both groups. Patients, clinicians, and research staff were unaware of the trial group assignments throughout the trial. Participants were unmasked once they had provided all outcome data at week 16–17, or sooner if a serious adverse event requiring knowledge of the study drug occurred. The dual primary outcome measures were worst and average pain scores assessed separately on a numerical rating scale in weeks 13–16 after randomisation, in the intention-to-treat population. Self-reported adverse events were assessed according to intention-to-treat principles. This trial is registered with the ISRCTN registry, ISCRTN77451762.FindingsParticipants were screened between Nov 30, 2015, and March 6, 2019, and 306 were randomly assigned (153 to gabapentin and 153 to placebo). There were no significant between-group differences in both worst and average numerical rating scale (NRS) pain scores at 13–16 weeks after randomisation. The mean worst NRS pain score was 7·1 (standard deviation [SD] 2·6) in the gabapentin group and 7·4 (SD 2·2) in the placebo group. Mean change from baseline was −1·4 (SD 2·3) in the gabapentin group and −1·2 (SD 2·1) in the placebo group (adjusted mean difference −0·20 [97·5% CI −0·81 to 0·42]; p=0·47). The mean average NRS pain score was 4·3 (SD 2·3) in the gabapentin group and 4·5 (SD 2·2) in the placebo group. Mean change from baseline was −1·1 (SD 2·0) in the gabapentin group and −0·9 (SD 1·8) in the placebo group (adjusted mean difference −0·18 [97·5% CI −0·71 to 0·35]; p=0·45). More women had a serious adverse event in the gabapentin group than in the placebo group (10 [7%] of 153 in the gabapentin group compared with 3 [2%] of 153 in the placebo group; p=0·04). Dizziness, drowsiness, and visual disturbances were more common in the gabapentin group.InterpretationThis study was adequately powered, but treatment with gabapentin did not result in significantly lower pain scores in women with chronic pelvic pain, and was associated with higher rates of side-effects than placebo. Given the increasing reports of abuse and evidence of potential harms associated with gabapentin use, it is important that clinicians consider alternative treatment options to off-label gabapentin for the management of chronic pelvic pain and no obvious pelvic pathology.FundingNational Institute for Health Research

Investigating neurodegeneration in a Drosophila model of tauopathy

Axonal degeneration occurring in disease is thought to be similar to that occurring after acute injury, known as Wallerian degeneration. Wallerian degeneration is an active process that can be delayed by the expression of the slow Wallerian degeneration (WldS) protein. In this project I sought to investigate whether WldS could delay axonal degeneration in a model of neurodegenerative disease: tauopathy. Tauopathy is characterised by neuronal dysfunction and degeneration occurring as a result of changes to the microtubule associated protein tau.Using Drosophila co-expressing htau0N3R and WldS, neuronal dysfunction was investigated in larvae. However, WldS did not improve tau-mediated deficits in axonal transport, synaptic alterations and locomotor behaviour, indicating WldS does not improve tau-mediated neuronal dysfunction. Furthermore, co-expression in the adult system, in which both neuronal dysfunction and degeneration occur, did not improve locomotor behaviour nor delay the onset or slow the progression of axonal swellings indicative of axonal degeneration. A significant increase in lifespan was observed, however as this was not accompanied by delayed axonal degeneration this is likely to be an off target effect. The failure of WldS to delay tau-mediated axonal degeneration suggests that a different mechanism controls axonal degeneration in disease than in injury. Supporting this, following axotomy htau0N3R;WldS axons displayed robust protection on a par with WldS axons. Interestingly, subsequent bystander protection against tau-mediated axonal swellings was observed in injured htau0N3R;WldS axons. This further supports that different mechanisms control axonal degeneration in chronic disease and acute injury.Mitochondria play an important role in neuronal dysfunction and degeneration in tauopathy, but how this contributes to axonal degeneration remains unclear. Expression of htau0N3R results in mitochondrial mislocalisation in the larval model of neuronal dysfunction. Restabilising the microtubule cytoskeleton using the drug NAP restored axonal transport but did not rescue mitochondrial mislocalisation, indicating that the mislocalisation is not simply due to the loss microtubule stabilisation by tau

Appendix 3. Study validity criteria

Appendix 3. Study validity criteri

Table 1. Characteristics of included studies

Table 1. Characteristics of included studie

Appendix 4. Reference list of studies included in meta-analysis

Appendix 4. Reference list of studies included in meta-analysi

Appendix 2. Search strategy

Appendix 2. Search strateg