Camilla Staahl

Subcutaneous Botulinum toxin type A reduces capsaicin-induced trigeminal pain and vasomotor reactions in human skin.

Abstract The present human study aimed at investigating the effect of subcutaneous administration of Botulinum toxin type A (BoNT/A) on capsaicin‐induced trigeminal pain, neurogenic inflammation and experimentally induced cutaneous pain modalities. Fourteen healthy males (26.3 ± 2.6 years) were included in this double‐blind and placebo‐controlled trial. The subjects received subcutaneous BoNT/A (22.5 U) and isotonic saline in the mirror sides of their forehead. Pain and neurogenic inflammation was induced by four intradermal injections of capsaicin (100 μg/μL) (before, and days 1, 3 and 7 after treatments). The capsaicin‐induced pain intensity, pain area, the area of secondary hyperalgesia, the area of visible flare and vasomotor reactions were recorded together with cutaneous heat, electrical and pressure pain thresholds. BoNT/A reduced the capsaicin‐induced trigeminal pain intensity compared to saline (F = 37.9, P < 0.001). The perceived pain area was smaller for the BoNT/A‐treated side compared to saline (F = 7.8, P < 0.05). BoNT/A reduced the capsaicin‐induced secondary hyperalgesia (F = 5.3, P < 0.05) and flare area (F = 10.3, P < 0.01) compared to saline. BoNT/A reduced blood flow (F1,26 = 109.5, P < 0.001) and skin temperature (F1,26 = 63.1, P < 0.001) at the capsaicin injection sites compared to saline and its suppressive effect was maximal at days 3 and 7 (P < 0.05, post hoc test). BoNT/A elevated cutaneous heat pain thresholds (F = 17.1, P < 0.001) compared to saline; however, no alteration was recorded for electrical or pressure pain thresholds (P > 0.05). Findings from the present study suggest that BoNT/A appears to preferentially target Cfibers and probably TRPV1‐receptors, block neurotransmitter release and subsequently reduce pain, neurogenic inflammation and cutaneous heat pain threshold.

Assessment of experimental pain from skin, muscle, and esophagus in patients with chronic pancreatitis

Objectives: Comprehensive experimental methods are of major relevance assessing pain mechanisms in patients with chronic pain. Chronic pancreatitis is thought to involve the sensory response in other visceral organs and somatic tissue. We, therefore, aimed at exploring the pain mechanisms in chronic pancreatitis (CP) using a multimodal and multitissue stimulation approach. Methods: Ten patients (mean age, 50 years) with CP and 13 healthy controls (mean age, 35 years) participated. None of the patients took analgesics regularly. All were exposed to multimodal (mechanical, thermal, and electrical) experimental pain in the skin, muscles, and esophagus. Results: The patients were hyposensitive to mechanical stimulations of the skin (P = 0.001), but there were no differences in the pain to thermal and electrical stimulations. In the muscle and esophagus, no differences in pain thresholds were found. The difference between single and repeated stimulations reflecting the degree of central sensitization was 17% in controls and 36% in patients (P = 0.001). The referred pain area to electrical stimulation was 30.1 cm2 in the patients and 7.7 cm2 for the controls (P = 0.02). Conclusions: The findings suggest that the balance among central hyperexcitability, neuroplastic changes, and descending pain-modulating pathways may explain the pain response to experimental multimodal stimulations in CP. This will likely also reflect the clinical pain mechanisms and may have important impact in selection of treatment, where drugs with potential effects on these mechanisms should be used.

Effect of transdermal opioids in experimentally induced superficial, deep and hyperalgesic pain

BACKGROUND AND PURPOSE Chronic pain and hyperalgesia can be difficult to treat with classical opioids acting predominately at the µ‐opioid receptor. Buprenorphine and its active metabolite are believed to act through µ‐, κ‐ and δ‐receptors and may therefore possess different analgesic and anti‐hyperalgesic effects compared with pure µ‐receptor agonists, for example, fentanyl. Here, we have compared the analgesic and anti‐hyperalgesic effects of buprenorphine and fentanyl.

Is electrical brain activity a reliable biomarker for opioid analgesia in the gut

The effects of morphine on brain potentials after experimental gut pain have never been investigated. This study explored whether multi-channel-evoked brain potentials (EP) and corresponding dipole sources in the brain would reflect the effects of morphine on experimental oesophageal pain. In a crossover study, the effects of oral morphine (30 mg) or corresponding placebo on pain from electrical oesophageal stimulation were tested in 12 healthy male volunteers. The electroencephalographic (EEG) activity was monitored with 64 surface recordings. Pain was assessed by subjective scores on a visual analogue scale, amplitude and latency of the vertex-EP as well as on multi-channel recordings of EPs. Finally, electrical brain sources after pain stimuli were modelled from the EEG data. Morphine attenuated subjective pain scores (p = 0.008). The amplitude of the P2 peak (230 msec. post-stimulus) in the vertex EPs was unaltered after treatment with morphine, whereas after placebo treatment, it decreased (p = 0.03). However, the overall topography changed and the source of P1 (100 msec. post-stimulus), possibly originating from areas near the cingulate gyrus, changed localization in an upward, posterior direction (p = 0.04). The length of the vector describing this shift correlated inversely with the magnitude of the subjective pain relief (r = -0.7; p = 0.02). With the potential of becoming a useful biomarker in analgesic trials, the localization of the dipole sources reflected the analgesic action of morphine after pain stimuli of the gut. Even though further evaluation of the method is necessary, it has the potential to be a valid objective biomarker for opioid analgesia.

The genetic influences on oxycodone response characteristics in human experimental pain

Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu‐, kappa‐ and delta‐opioid receptor genes (OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold (PTT) (n = 37), muscle pressure PTT (n = 31), mechanical visceral PTT (n = 43) and thermal visceral PTT (n = 41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single‐nucleotide polymorphisms (SNPs) rs589046 (P < 0.0001) and rs563649 (P < 0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 (P = 0.015), rs1799971 (P = 0.045), rs9479757 (P = 0.009) and rs533586 (P = 0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance (P = 0.015). Another OPRD1 SNP rs2234918 (P = 0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone.

The absorption profile of pregabalin in chronic pancreatitis.

It was recently shown that pregabalin decreased pain associated with chronic pancreatitis. It is well known that pancreatitis patients suffer from fat malabsorption with accompanying diarrhoea because of loss of exocrine pancreatic enzyme production. This may lead to changes in the mucosal surface in the small intestine and possibly affect the absorption of pregabalin. The pharmacokinetics of pregabalin has never been investigated in patients suffering from chronic pancreatitis. The aim of this study was to develop a population pharmacokinetic model of pregabalin administered to patients with chronic pancreatitis. The pregabalin population pharmacokinetic analysis was conducted on data from fifteen patients with chronic pancreatitis. Each patient received 75 mg of pregabalin (oral capsule). Pregabalin concentrations were measured using a validated liquid chromatographic method. Data analysis was performed using non‐linear mixed effects modelling methodology as implemented by NONMEM. A one‐compartment model with first‐order absorption and elimination adequately described pregabalin pharmacokinetics. Time to maximum observed plasma concentration (Tmax) was 1.53 (95% CI 1.09–2.05). The maximum plasma concentration (Cmax) was 1.98 μg/ml (95% CI 1.69–2.34), and area under the plasma concentration–time profile (area under the curve) was 18.2 μg*hr/ml (95% CI 14.7–26.3). Pregabalin is well absorbed in patients with chronic pancreatitis, and the pharmacokinetic profile of pregabalin is not extensively affected by chronic pancreatitis.