Peter Drummond

Background
Migraine headache and complex regional pain syndrome share mechanisms, such as neuroinflammation, central sensitization and loss of inhibitory pain controls, that could provoke or exacerbate symptoms in both disorders. In the present study, it was hypothesized that headaches would worsen after the onset of complex regional pain syndrome and that limb pain would be more severe in patients with co-morbid headaches than in patients who remained headache-free. Notably, complex regional pain syndrome is associated with ipsilateral cranial symptoms such as photophobia and forehead hyperalgesia. Whether shared mechanisms might drive these symptoms was also explored.

Methods
Eighty-eight patients with complex regional pain syndrome were asked about their previous and current headache experience. The spatial distribution of pain was quantified from pain drawings, and hyperalgesia to mechanical and thermal stimulation was assessed in the limbs and forehead. In addition, the visual discomfort threshold was measured separately for each eye.

Results
Sixty-six percent of patients reported that headaches (primarily migraine) had developed or worsened after the onset of complex regional pain syndrome and 22 percent now had daily or near-daily headaches. Limb pain and hyperalgesia were greater in such cases than in those with stable headaches or who remained headache-free. Photophobia and forehead hyperalgesia were greater ipsilateral than contralateral to symptoms of complex regional pain syndrome in patients with stable or worsening headaches but were symmetrical in headache-free patients. In addition, photophobia was symmetrical in patients with recurrent tension-type headaches. Patients with worsening headaches were younger at the onset of complex regional pain syndrome than patients with stable headaches or who were headache-free, in line with greater vulnerability to migraine in younger than older adults. In a subgroup of patients, the pain of complex regional pain syndrome extended from the upper limb to the ipsilateral dorsal cervical region, a documented source of pain in migraine. However, headaches ipsilateral to complex regional pain syndrome also recurred in patients with lower limb pain, indicating involvement of other pain mechanisms.

Conclusions
Together, the findings indicate that headaches with features of migraine develop after the onset of complex regional pain syndrome. In turn, this is associated with ipsilateral cranial symptoms and heightened limb pain. We suggest that shared pathophysiology increases susceptibility to ipsilateral cranial symptoms and exacerbates pain in both disorders, potentially in a positive loop. Breaking this cycle might permit otherwise intractable symptoms and pain to subside.

Complex regional pain syndrome (CRPS) involves disproportionate chronic pain alongside sensory, autonomic, motor, and trophic disturbances. The pathophysiology of CRPS remains unclear, but evidence indicates that cutaneous neuroimmune dysregulation contributes to symptom onset and maintenance. We conducted a high-parameter imaging mass cytometry and targeted immunofluorescence study of skin biopsies from 18 CRPS patients and 18 healthy controls using a panel of heavy metal isotope-conjugated antibodies to assess nerve fibre, immune cell, and vascular markers in situ. Quantitative data analysis revealed a reduction in proliferating keratinocytes, increased human leukocyte antigen-DR+ (HLA-DR+) Langerhans cell (LC) abundance, and increased HLA-DR+ LC physiological interactions with intraepidermal nerve fibres in patients with CRPS. Langerhans cells also showed sexual dimorphism, being higher in CRPS-affected skin in women compared with men. HLA-DR+CD206− dermal dendritic cells (DC) and CD68+CXCR3+ pro-inflammatory macrophages were increased in CRPS-affected skin. Nerve fibre and blood vessel densities were unchanged. However, intraepidermal nerve fibre density decreased in proportion to temperature asymmetry between disease-affected and contralateral unaffected limbs, being lowest in patients with a cool CRPS-affected limb. These findings highlight significant decreases in epidermal keratinocyte proliferation, increases in LC abundance and nerve fibre interactions, especially the HLA-DR+ subset, and increases in dermal DC cells in CRPS-affected skin, supporting a role for neuroimmune dysfunction and autoimmunity in CRPS pathophysiology.

Posttraumatic stress disorder (PTSD) and chronic pain (CP) are highly co-occurring conditions, characterised by poor treatment outcomes and shared mechanisms that exacerbate symptom severity and functional impairment. This randomised, waitlist-controlled trial evaluated the efficacy of a six-week heart rate variability biofeedback (HRVBF) intervention in improving concurrent symptoms of PTSD and CP. Data of 73 Australian participants (mean age: 42.2; 14 male, 59 female), meeting clinical criteria for both conditions, were analysed following either six weeks of HRVBF or waitlist control. Symptom changes were assessed using validated psychometric measures. The HRVBF group demonstrated significant reductions in PTSD symptoms, with a 24.3 % decrease in PTSD Checklist total scores (d = −0.02) and improvement across all symptom clusters, compared to no significant change in the waitlist group. Similarly, trauma-related distress (Impact of Events Scale) decreased by 18.9 % (d = 0.03) post-intervention. Pain interference (Brief Pain Inventory – short form) improved significantly (24.9 % reduction; d = 0.19), whereas reductions in pain intensity and pain disability did not differ significantly between groups. These results highlight the potential of HRVBF as an effective intervention for co-occurring PTSD and CP.

Pain often spreads away from the injured site in complex regional pain syndrome (CRPS), but what drives this process is unclear. To explore this, pain drawings were investigated in 136 patients in relation to the type and location of injury, pain intensity and quality, CRPS duration, subtypes, and hyperalgesia to thermal and mechanical stimuli. Areas of pain were quantified using the ImageJ polygon selection tool. The pain area in the affected limb increased in line with pain intensity and with indices of hyperalgesia in the affected limb and ipsilateral forehead ( P 's < 0.01). The pain area was greater in patients with proximal than distal limb injury, CRPS I than II, longstanding than acute CRPS, the warm than symmetrical or cold subtypes, and in patients who experienced burning pain and/or pins-and-needles ( P 's < 0.05). Together, these predictors accounted for 30.4% of variance in pain area in the affected limb ( P < 0.001). Thirty-five patients were reassessed after 5 to 124 months. After an invasive treatment such as an electrical stimulator implant or sympathetic blockade (N = 20), the pain area decreased in the affected limb of 11 patients but increased in 9 others. The pain area increased during follow-up in most other patients, and pain developed spontaneously in a previously unaffected limb in a minority of cases—specifically, in those with a greater area of pain and stronger hyperalgesia in the affected limb at baseline. Together, the findings suggest that peripheral and/or central nociceptor sensitization is associated with pain expansion in CRPS.

Although the association between stress and pain is recognised, little is known about links between chronic pain and stress arising from perfectionist expectations. Two studies compared levels of socially prescribed perfectionism (SPP), self-oriented perfectionism (SOP), self-compassion (SC), and self-efficacy (SE) between individuals with and without chronic pain. In Study 1, 237 participants with chronic pain and 237 without pain completed an online survey. Participants with chronic pain had significantly higher levels of SPP and lower levels of SC than those without pain. However, there were no differences in SOP or SE. In Study 2, 294 individuals with chronic pain, and 278 without, completed an online survey. Individuals with chronic pain reported significantly higher levels of perfectionism and lower levels of SC and SE than pain-free individuals. SPP and SOP were higher in those with low SC scores. Correlation analyses identified that SOP and SC were positively associated with SE whereas SPP was associated negatively with SE. These findings largely align with the perfectionism social disconnection model. A clearer understanding of the inter-relationships between perfectionism and protective factors, such as SC and SE, has important implications for those experiencing chronic pain conditions, including potential pain management interventions and long-term wellbeing.

Introduction
Opioid sparing by co-prescription of cannabinoids may enable patients to reduce their opioid consumption prescribed for chronic benign pain.

Methods
One cohort attending a small private pain clinic (N = 102), already taking opioids, was co-prescribed cannabinoids and another cohort (N = 53) attending a separate pain clinic nearby received only opioids. The two groups were studied prospectively for a year before their drug consumption was assessed.

Results
At baseline, median opioid consumption was 40 mg/day in both cohorts. Medicinal cannabis was administered daily in an oil formulation usually starting at 2.5 mg/day and was titrated to maximize benefits. At 12 months, the median dose contained 15 mg delta-9-tetrahydrocannabinol and 15 mg cannabidiol. At one-year follow-up, 46 of 102 cases had dropped out compared with only one of 53 controls. Opioid consumption had decreased significantly at one-year follow-up, the final median dose being lower in cases (2.7 mg/day) than controls (42.3 mg/day) (p < 0.05 in an intention-to-treat analysis). Disability and insomnia had also decreased in cases.

Conclusion
The introduction of cannabinoids can produce useful reductions in opioid consumption in real-world settings, with additional benefits for disability and insomnia. However, this treatment is tolerated by only a subgroup of patients.

Objective
Tremor is one of the most common motor symptoms of Parkinson’s disease (PD), with adverse effects on daily functioning and quality of life. This study investigated the effects of concurrent intermittent theta-burst stimulation and gamma frequency transcranial alternating current stimulation (iTBS-γ-tACS) on neuroplasticity in the motor cortex and resting tremor severity in individuals with tremor-dominant PD.

Methods
Eighteen individuals (mean age 66.8 ± 10.0 years, 6 females) with tremor-dominant PD attended two sessions, one involving iTBS-γ-tACSreal (real iTBS and real tACS), and the other involving iTBS-γ-tACSsham (real iTBS and sham tACS). Measures of neuroplasticity (corticospinal excitability and intracortical inhibition) and tremor severity were measured before and after iTBS-γ-tACS.

Results
Corticospinal excitability in the target muscle increased significantly after iTBS-γ-tACSreal, but not iTBS-γ-tACSsham. Intracortical inhibition and tremor severity were not significantly modulated by either stimulation condition.

Conclusions
iTBS-γ-tACSreal, but not iTBS-γ-tACSsham, elicited long-term potentiation-like neuroplastic changes in the target muscle.

Significance
This is the first study to show iTBS-γ-tACS can induce neuroplasticity in individuals with tremor-dominant PD. Despite no significant changes in tremor severity, future research should explore if targeting neuroplasticity in the cortical representation of the tremor-dominant muscle and/or multi-session administrations of iTBS-γ-tACS can reduce tremor.

Abstract
Resting tremor—involuntary and rhythmic shaking that usually occurs in the limbs—is the most common presenting motor symptom in Parkinson’s disease (PD). Tremor is not associated with the severity of dopamine depletion in the basal ganglia, and dopaminergic medication, which is used primarily to target dopamine depletion in the basal ganglia, has limited efficacy in reducing tremor. This suggests that other brain regions might underpin tremor in PD. Intracortical inhibition within the primary motor cortex (M1) has been implicated in tremor: intracortical inhibition in M1 is lower in PD than controls, higher motor cortex GABA is associated with lower tremor severity in PD, and pharmacological increases in GABA activity reduce tremor severity in PD. A combined intermittent theta-burst stimulation (iTBS)—gamma transcranial alternating current stimulation (tACS) protocol has been shown to increase short-interval intracortical inhibition (SICI) in PD. Therefore, in the current study, we examined M1 excitability, SICI, and resting tremor before and after real and sham iTBS-tACS. In a within-subjects design, we tested 19 participants (13 male; mean age 66 years) with idiopathic, tremor-dominant PD OFF medication. M1 excitability increased after real but not sham iTBS-tACS. There was no change in SICI after either real or sham iTBS-tACS. Resting tremor in the extensor carpi radialis showed a trend to increase after sham but not real iTBS, indicating that real iTBS-tACS might have prevented resumption of tremor activity in PD participants OFF medication. These findings provide preliminary evidence that iTBS-tACS induced long-term potentiation-like plasticity in M1 in tremor-dominant PD, which could influence tremor severity. However, further research is needed to examine the time-course of iTBS-tACS-induced changes in M1 excitability and tremor severity. If iTBS-tACS can reduce tremor, it could offer an alternative, or supplementary, treatment to levodopa medication for people with tremor-dominant PD.

Research Category and Technology and Methods
Clinical Research: 10. Transcranial Magnetic Stimulation (TMS)

The aim of this study was to identify methodological issues that might influence comparison of burst versus sham spinal cord stimulation for treating chronic pain. Six patients with an implanted BurstDR spinal cord stimulator were assessed double-blind during eight 3-to-4-day ON or OFF cycles over a 28-day period. The stimulator was switched off during two randomly selected cycles. Pain intensity was the primary outcome, and secondary outcomes included analgesic consumption, activity estimation and sleep quality. To minimise stimulation wash-in and wash-out effects, ratings during the first two days of each cycle, or where rescue medication was taken, were discarded. Mean ratings during ON versus OFF cycles were compared using Wilcoxon’s signed-ranks test. Pain ratings averaged 4.1 ± 2.0 during OFF cycles and 3.9 ± 2.5 during ON cycles (difference not significant). However, ratings were one or more points higher during OFF than ON cycles in two patients with recent stimulator implants who correctly identified the stimulator status during most cycles. Patients were more refreshed on waking during ON than OFF cycles but burst stimulation did not influence ratings of pain interference, mood, sensitivity to mechanical stimulation or consumption of rescue medication. The findings in our case series point to the importance of investigating individual differences in response to burst spinal cord stimulation. To establish whether this treatment is effective for managing chronic pain, selecting patients with short wash-in and wash-out times, or including lengthy periods of wash-in and wash-out in the study protocol, is crucial. Selection criteria should also include pain ratings at entry of 3 or less on a 0-10 scale; stable physical and psychological functioning with little disability; minimal rescue medication; and patients who take less than 50 morphine equivalents per day.