Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized,double-blind,placebo-controlled,crossover study in healthy volunteers

Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5 mg), placebo, or morphine (10 mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5 mg) elicited higher peak analgesia (105, 116 seconds latency vs 75 seconds for morphine, P < .02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180 seconds) with TRV130 (3, 4.5 mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (−15.9 for morphine versus −7.3, −7.6, and −9.4 h * L/min, P < .05). More subjects experienced severe nausea after morphine (n = 7) than TRV130 1.5 or 3 mg (n = 0, 1), but not 4.5 mg (n = 9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.     

Endogenous opioid function mediates the association between laboratory-evoked pain sensitivity and morphine analgesic responses

Predictors of responsiveness to opioid analgesic medications are not well understood. This study tested whether individual differences in endogenous opioid (EO) function are associated with analgesic responsiveness to morphine. In randomized, counterbalanced order over 3 sessions, 45 chronic low back pain participants and 31 healthy controls received an opioid antagonist (8 mg naloxone), morphine (0.08 mg/kg), or placebo. Participants then engaged in 2 laboratory-evoked pain tasks (ischemic and thermal). Outcomes included pain threshold, pain tolerance, and pain ratings. Indexes of EO function and morphine analgesic responsiveness were derived for each measure as the difference in pain responses between the placebo condition and naloxone or morphine condition, respectively. For all 7 pain measures across the 2 laboratory pain tasks, greater EO function was associated with significantly lower morphine analgesic responsiveness (P < 0.001–P = 0.02). Morphine reduced pain responses of low EO individuals to levels similar to those of high EO individuals receiving placebo. Higher placebo condition–evoked pain sensitivity was associated with significantly greater morphine analgesic responsiveness for 5 of 7 pain measures (P < 0.001–P = 0.02). These latter associations were significantly mediated by EO function for 4 of these 5 pain outcomes (all P values < 0.05). In the laboratory-evoked pain context, opioid analgesic medications may supplement inadequate EO analgesia, with little incremental benefit in those with preexisting high EO function. Implications for personalized medicine are discussed.     

Evaluation of menstrual cycle effects on morphine and pentazocine analgesia

Studies have demonstrated menstrual cycle influences on basal pain perception, but direct evidence of menstrual cycle influences on analgesic responses has not been reported in humans. Our aim was to determine whether the magnitude of morphine and pentazocine analgesia varied across the menstrual cycle. Sixty-five healthy women, 35 taking oral contraceptives (OC) and 30 normally cycling (NOC), underwent experimental pain assessment both before and after intravenous administration morphine (0.08 mg/kg) or pentazocine (0.5 mg/kg) compared to saline placebo. Both active drug and placebo were administered once during the follicular phase and once during the luteal phase. Measures of heat, ischemic, and pressure pain sensitivity were obtained before and after drug administration. Change scores in pain responses were computed to determine morphine and pentazocine analgesic responses, and medication side effects were recorded. The data were analyzed using mixed-model analyses of variance. NOC women showed slightly greater heat pain sensitivity in the follicular vs luteal phase, while the reverse pattern emerged for OC women (P = 0.046). Also, OC women showed lower pressure pain thresholds compared to NOC women (P < 0.05). Regarding analgesic responses, NOC women showed greater morphine analgesia for ischemic pain during the follicular vs the luteal phase (P = 0.004). Likewise, side effects for morphine were significantly higher in NOC women in the follicular phase than in the luteal phase (P = 0.02). These findings suggest that sex hormones may influence opioid responses; however, the effects vary across medications and pain modalities and are likely to be modest in magnitude.     

Do sex differences exist in opioid analgesia? A systematic review and meta-analysis of human experimental and clinical studies

Although a contribution of sex in opioid efficacy has garnered much attention, the confirmation and direction of any such difference remain elusive. We performed a systematic review of the available literature on sex differences in μ and mixed μ/κ opioid effect on acute and experimental pain. Fifty unique studies (including three unpublished studies) were included in the analyses. Across the 25 clinical studies on μ-opioids there was no significant sex-analgesia association. Restricting the analysis to patient-controlled analgesia (PCA) studies (irrespective of the opioid) yielded greater analgesia in women (n = 15, effect size 0.22, 95% c.i. 0.02-0.42, P = 0.028). Further restricting the analysis to PCA morphine studies yielded an even greater effect in women (n = 11, effect size = 0.36, 95% c.i. 0.17-0.56, P = 0.003). Meta-regression indicated that the longer the duration of PCA, the difference in effect between the sexes further increased. Across experimental pain studies on μ-opioids women had greater antinociception from opioids (n = 11, effect size = 0.35; 95% c.i. 0.01-0.69, P = 0.047), which was predominantly due to 6 morphine studies. Female patients had greater μ/κ opioid analgesia (n = 7, effect size 0.84; 95% c.i. 0.25-1.43, P = 0.005), but no sex-analgesia association was present in experimental studies (n = 7). Sex differences exist in morphine-induced analgesia in both experimental pain studies and clinical PCA studies, with greater morphine efficacy in women. The data on non-morphine μ and mixed μ/κ-opioids are less convincing and require further study.     

A phase 2, double-blind,randomized, placebo-controlled,dose-escalation study to evaluate the efficacy,safety, and tolerability of naloxegol in patients with opioid-induced constipation

Naloxegol (previously known as NKTR-118) is a peripherally acting μ-opioid receptor antagonist engineered using polymer conjugate technology in development as an oral, once-daily agent for the treatment of opioid-induced constipation (OIC). Eligible patients with OIC (n = 207), defined as <3 spontaneous bowel movements (SBMs) per week with accompanying symptoms, on a stable opioid regimen of 30–1000 mg/day morphine equivalents for ?2 weeks were randomized to receive 4 weeks of double-blind placebo or naloxegol (5, 25, or 50 mg) once daily in sequential cohorts after a 1-week placebo run-in. The primary end point, median change from baseline in SBMs per week after week 1 of drug administration, was statistically significant for the 25- and 50-mg naloxegol cohorts vs placebo (2.9 vs 1.0 [P = 0.0020] and 3.3 vs 0.5 [P = 0.0001], respectively). The increase in SBMs vs placebo was maintained over 4 weeks for naloxegol 25 mg (3.0 vs 0.8 [P = 0.0022]) and 50 mg (3.5 vs 1.0 [P < 0.0001]). Naloxegol was generally well tolerated across all dosages. The most frequent adverse events (AEs) were abdominal pain, diarrhea, and nausea. Most AEs at 5 and 25 mg/day were mild and transient. Similar AEs occurred with increased frequency and severity in the 50-mg cohort. There was no evidence of a statistically significant increase from baseline in pain, opioid use for the 25- and 50-mg cohorts, or centrally mediated opioid withdrawal signs and/or symptoms with naloxegol. These data demonstrate that once-daily oral naloxegol improves the frequency of SBMs compared with placebo and is generally well tolerated in this population of patients with OIC.     

Is the pain-reducing effect of opioid medication reliable? A psychophysical study of morphine and pentazocine analgesia

A number of laboratory studies have confirmed the efficacy of opioid medication in reducing pain generated by a number of psychophysical modalities. However, one implicit assumption of clinical and experimental pain testing of analgesics is that the analgesic response is stable and will be comparable across repeated administrations. In the current study, the repeatability of opioid analgesia was assessed in a randomized, double-blinded study using 3 psychophysical pain modalities (e.g., thermal, pressure, and ischemic) over 4 medication sessions (2 with active drug, 2 with placebo). Psychophysical responses were evaluated before and after intravenous administration of either morphine (0.08 mg/kg; n = 52) or pentazocine (0.5 mg/kg; n = 49). To determine the ability of a drug to reduce pain, 4 analytic methods (i.e., absolute change, percent change, ratio, and residualized change scores) were calculated to generate separate analgesic index scores for each measure and drug condition. All analgesic index scores demonstrated a greater analgesic response compared to saline for both medications, but stability (i.e., test-retest correlations) of the opioid analgesic indices depended on the pain measurement. Ischemic pain outcomes were moderately stable across sessions for both opioid medications; however, heat and pressure analgesic index scores were moderately stable for only morphine and pentazocine, respectively. Finally, within stimulus modalities, analgesic index scores were highly correlated with each other, suggesting that the different methods for computing analgesic responses provided comparable results. These results suggest that analgesic measures are able to distinguish between active drugs. In addition, analgesic responses to morphine and pentazocine demonstrate at least moderate reliability.     

The effects of depression and smoking on pain severity and opioid use in patients with chronic pain

Depression and smoking are common comorbid conditions among adults with chronic pain. The aim of this study was to determine the independent effects of depression on clinical pain and opioid use among patients with chronic pain according to smoking status. A retrospective design was used to assess baseline levels of depression, clinical pain, opioid dose (calculated as morphine equivalents), and smoking status in a consecutive series of patients admitted to a 3-week outpatient pain treatment program from September 2003 through February 2007. Depression was assessed using the Centers for Epidemiologic Studies-Depression scale, and clinical pain was assessed using the pain severity subscale of the Multidimensional Pain Inventory. The study cohort (n = 1241) included 313 current smokers, 294 former smokers, and 634 never smokers. Baseline depression (P = .001) and clinical pain (P = .001) were greater among current smokers compared to former and never smokers, and the daily morphine equivalent dose was greater among smokers compared to never smokers (P = .005). In multivariate linear regression analyses, baseline pain severity was independently associated with greater levels of depression, but not with smoking status. However, status as a current smoker was independently associated with greater opioid use (by 27 mg/d), independent of depression scores. The relationship between depression, smoking status, opioid use, and chronic pain is complex, and both depression and smoking status may be potentially important considerations in the treatment of patients with chronic pain who utilize opioids.     

An enriched-enrolment,randomized withdrawal,flexible-dose,double-blind,placebo-controlled,parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain

Cannabinoids are emerging as potential options for neuropathic pain treatment. This study evaluated an oral cannabinoid, nabilone, in the treatment of refractory human diabetic peripheral neuropathic pain (DPN). We performed a single-center, randomized, double-blind, placebo-controlled, flexible-dose study with an enriched enrolment randomized withdrawal design. DPN subjects with a pain score ?4 (0-10 scale) continued regular pain medications and were administered single-blinded adjuvant nabilone for 4 weeks. Subjects achieving ?30% pain relief (26/37) were then randomized and treated with either flexible-dose nabilone 1-4 mg/day (n = 13) or placebo (n = 13) in a further 5-week double-blind treatment period, with 30% (11/37) of subjects deemed run-in-phase nabilone nonresponders. For nabilone run-in-phase responders, there was an improvement in the change in mean end-point neuropathic pain vs placebo (mean treatment reduction of 1.27; 95% confidence interval 2.29-0.25, P = 0.02), with an average nabilone dose at end point of 2.9 ± 1.1 mg/day, and improvements from baseline for the anxiety subscale of the Hospital Anxiety and Depression Scale, the Medical Outcomes Study sleep scale problems index, and the European Quality of Life-5-Domains index score (each P < 0.05). Nabilone run-in-phase responders reported greater global end-point improvement with nabilone than with placebo (100% vs 31%; P < 0.05). Medication-related confusion led to discontinuation in 2/37 subjects during single-blind nabilone treatment. Potential unmasking occurred in 62% of both groups. Flexible-dose nabilone 1-4 mg/day was effective in relieving DPN symptoms, improving disturbed sleep, quality of life, and overall patient status. Nabilone was well tolerated and successful as adjuvant in patients with DPN.     

Morphine consumption is not modified in patients with severe pain and classified by the DN4 score as neuropathic

Neuropathic pain has been poorly investigated in the emergency department, although it is known to be less sensitive to opioids than other forms of pain. We tested the hypothesis that morphine requirements are increased in patients having severe pain classified as neuropathic using the DN4 score. We included adult patients with acute severe pain (visual analog scale ≥ 70), assessed using the DN4 score, and treated with intravenous morphine titration (bolus of 2 or 3 mg [body weight > 60 kg] with 5-minute intervals between each bolus). Pain relief was defined as a visual analog scale 30 or less. Patients were divided into 2 groups: control group (DN4 score < 4) and neuropathic pain group (DN4 score ≥ 4). The main outcome was the total dose of morphine administered. Data are mean ± SD or median (interquartile range). Among the 239 patients included (mean age, 43 + 14 years), 35 patients (15%) had a DN4 score 4 or more. The main characteristics of the 2 groups were comparable. There were no significant differences between the 2 groups in morphine dose (0.16 + 0.09 vs 0.17 + 0.11 mg/kg, P = .32), number of boluses administered (3.5 [3-5] vs 3 [3-6], P = .97), proportion of patients with pain relief (75 vs 83%, P = .39), or morphine-related adverse effects (11% vs 3%, P = .14). In conclusion, morphine consumption was not significantly modified in patients having severe pain classified as neuropathic using the DN4 score as compared with a control group, suggesting that specific detection of neuropathic pain may not be useful in the emergency department.     

Deciphering the role of endogenous opioids in high-frequency TENS using low and high doses of naloxone

Previous human studies have shown that the analgesic effect of high-frequency TENS could not be reversed by low doses of naloxone. The aim of the present study was to reinvestigate the possible contribution of opioid receptors to high-frequency TENS analgesia by using low (0.02 mg/kg) and high (0.14 mg/kg) doses of naloxone. Naloxone (high and low doses) and saline were administered intravenously to young healthy adults using a triple-blind randomized cross-over design. For each visit, TENS (100 Hz, 60 μs) was applied for 25 min to the external surface of the left ankle. TENS intensity was adjusted to obtain strong but comfortable (innocuous) paresthesias. Experimental pain was evoked with a 1 cm² thermode applied on the lateral aspect of the left heel. Subjective pain scores were obtained before, during and after TENS. Because preliminary analyses showed that the order of presentation affected the pattern of results, only the first visit of every participant could be analyzed without fear of contamination from possible carry-over effects. These revealed that TENS maintained its analgesic properties following the injection of saline (p < .001) and the injection of a low dose of naloxone (p < .05). However, when a high dose of naloxone was administered, TENS analgesia was completely blocked (p = .20). These results suggest that high-frequency TENS involves opioid receptors. An insufficient amount of opioid antagonist likely prevented previous human studies from discovering the importance of opioid receptors in producing high-frequency TENS analgesia.     

Lack of endogenous opioid release during sustained visceral pain: A [C]carfentanil PET study

Opioidergic neurotransmission in the central nervous system is involved in somatic pain, but its role in visceral pain remains unknown. We aimed to quantify endogenous opioid release in the brain during sustained painful gastric distension. Therefore, 2 dynamic [¹¹C]carfentanil positron emission tomography scans were performed in 20 healthy subjects during 2 conditions: sustained (20 minutes) painful proximal gastric balloon distension at predetermined individual discomfort threshold (PAIN) and no distension (NO PAIN), in counterbalanced order. Pain levels were assessed during scanning using visual analogue scales and after scanning using the McGill Pain Questionnaire. Emotional state was rated after scanning using the Positive and Negative Affect Schedule. Distribution volume ratios in 21 volumes of interest in the pain matrix were used to quantify endogenous opioid release. During the PAIN compared to the NO PAIN condition, volunteers reported a significantly higher increase in negative affect (5.50 ± 1.29 versus 0.10 ± 1.08, P = .0147) as well as higher pain ratings (sensory: 74.05 ± 9.23 versus 1.50 ± 0.95, P < .0001; affective: 91.42 ± 8.13 versus 4.33 ± 6.56, P < .0001). No difference in endogenous opioid release was demonstrated in any of the volumes of interest. Thus, contrary to its somatic counterpart, no opioid release is detected in the brain during sustained visceral pain, despite similar pain intensities. Endogenous opioids may play a less important role in visceral compared to somatic pain.     

Pain in chemotherapy-induced neuropathy – More than neuropathic?

Chemotherapy-induced neuropathy (CIN) is an adverse effect of chemotherapy. Pain in CIN might comprise neuropathic and nonneuropathic (ie, musculoskeletal) pain components, which might be characterized by pain patterns, electrophysiology, and somatosensory profiling. Included were 146 patients (100 female, 46 male; aged 56 ± 0.8 years) with CIN arising from different chemotherapy regimens. Patients were characterized clinically through nerve conduction studies (NCS) and quantitative sensory testing (QST). Questionnaires for pain (McGill) and anxiety/depression (Hospital Anxiety and Depression Scale) were supplied. Patients were followed-up after 17 days. Large- (61%) and mixed- (35%) fibre neuropathies were more frequent than small-fibre neuropathy (1.4%). The 5 major chemotherapeutic regimens impacted differently on large- but not on small-fibre function and did not predict painfulness. Chronic pain associated with CIN was reported in 41.7%. Painless and painful CIN did not differ in QST profiles or electrophysiological findings, but different somatosensory patterns were found in CIN subgroups (pain at rest [RestP], n = 25; movement-associated pain [MovP], n = 15; both pain characteristics [MovP+RestP], n = 21; or no pain [NonP], n = 85): small-fibre function (cold-detection threshold, CDT: z score: −1.46 ± 0.21, P < 0.01) was most impaired in RestP; mechanical hyperalgesia was exclusively found in MovP (z score: +0.81 ± 0.30, P < 0.05). “Anxiety” discriminated between painful and painless CIN; “CDT” and “anxiety” discriminated between patients with ongoing (RestP) and movement-associated pain (MovP) or pain components (MovP+RestP). The detrimental effect of chemotherapy on large fibres failed to differentiate painful from painless CIN. Patients stratified for musculoskeletal or neuropathic pain, however, differed in psychological and somatosensory parameters. This stratification might allow for the application of a more specific therapy.     

Time-scheduled vs. pain-contingent opioid dosing in chronic opioid therapy

Some expert guidelines recommend time-scheduled opioid dosing over pain-contingent dosing for patients receiving chronic opioid therapy (COT). The premise is that time-scheduled dosing results in more stable opioid blood levels and better pain relief, fewer adverse effects, less reinforcement of pain behaviors, and lower addiction risk. We report results of a survey of 1781 patients receiving COT for chronic noncancer pain, in which 967 reported time-scheduled opioid dosing only and 325 reported pain-contingent opioid dosing only. Opioid-related problems and concerns were assessed with the Prescribed Opioids Difficulties Scale. We hypothesized that respondents using time-scheduled opioid dosing would report significantly fewer problems and concerns than those using pain-contingent dosing. Patients receiving time-scheduled dosing received substantially higher average daily opioid doses than those using pain-contingent dosing (97.2 vs. 37.2 mg average daily dose morphine equivalents, P < .0001). Contrary to expectation, time-scheduled opioid dosing was associated with higher levels of patient opioid control concerns than pain-contingent dosing (6.2 vs. 4.8, P = .008), after adjusting for patient and drug regimen differences. Opioid-related psychosocial problems were somewhat greater among patients using time-scheduled dosing, but this difference was nonsignificant after controlling for patient and drug regimen differences (5.9 vs. 5.0, P = .14). Time-scheduled dosing typically involved higher dosage levels and was associated with higher levels of patient concerns about opioid use. Controlled comparative effectiveness research is needed to assess benefits and risks of time-scheduled opioid dosing relative to pain-contingent opioid dosing among COT patients in ambulatory care.     

Pregabalin in severe burn injury pain: a double-blind, randomised placebo-controlled trial

This randomised, double-blind, placebo-controlled trial assessed the efficacy and tolerability of pregabalin to alleviate the neuropathic component of moderate to severe burn pain. Patients aged 18 to 65 years admitted to a burns unit with a 5% or greater total body surface area burn injury were screened to participate in the trial. Using the Neuropathic Pain Scale (NPS), patients scoring 4 or higher on ‘hot’ pain or ‘sharp’ pain were invited to participate. Consenting patients were randomly assigned to receive pregabalin or placebo for 28 days with individual dose titration commencing at 75 mg twice daily to a maximum pregabalin dose of 300 mg twice daily. The primary outcome measure was the patients’ daily response to the sharp and hot pain of the NPS. Secondary outcome measures included the remaining elements of the NPS, daily opioid requirement, length of hospital stay, pain at 6 months, and side effects of nausea, vomiting, drowsiness and giddiness. For patients administered pregabalin, the primary outcome measures hot (P = .01) and sharp (P = .04) pain were significantly reduced compared with those in patients administered placebo. Secondary outcome measures of itch, unpleasantness, surface pain, and procedural pain were significantly lower (P < .05) in the pregabalin group. Adverse effects were uncommon, with no difference between the treatment groups. There was no significant difference between the pregabalin and placebo treatment groups with respect to opioid consumption, duration of hospital stay, or pain at 6 months. Pregabalin was efficacious and well tolerated in patients after severe burn injury and whose pain was characterised by features of acute neuropathic pain.     

Safety and efficacy of pregabalin in patients with central post-stroke pain

Pregabalin has demonstrated efficacy in several forms of neuropathic pain, but its long-term efficacy in central post-stroke pain (CPSP) is unproven. We evaluated the efficacy and safety of pregabalin versus placebo in patients with CPSP. A 13-week, randomized, double-blind, multicenter, placebo-controlled, parallel group study of 150 to 600 mg/day pregabalin was conducted in patients aged ?18 years with CPSP. The primary efficacy endpoint was the mean pain score on the Daily Pain Rating Scale over the last 7 days on study drug up to week 12 or early termination visit. Secondary endpoints included other pain parameters and patient-reported sleep and health-related quality-of-life measures. A total of 219 patients were treated (pregabalin n = 110; placebo n = 109). A mean pain score at baseline of 6.5 in the pregabalin group and 6.3 in the placebo group reduced at endpoint to 4.9 in the pregabalin group and 5.0 in the placebo group (LS mean difference = -0.2; 95% CI = -0.7, 0.4; P = 0.578). Treatment with pregabalin resulted in significant improvements, compared with placebo, on secondary endpoints including MOS-sleep, HADS-A anxiety, and clinician global impression of change (CGIC) P < 0.05. Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 9 (8.2%) of pregabalin patients versus 4 (3.7%) of placebo patients. Although pain reductions at endpoint did not differ significantly between pregabalin and placebo, improvements in sleep, anxiety, and CGIC suggest some utility of pregabalin in the management of CPSP.     

Modulation of inhibitory neurotransmission by the vanilloid receptor type 1 (TRPV1) in organotypically cultured mouse substantia gelatinosa neurons

The vanilloid receptor type 1 (TRPV1) plays a pivotal role in modulating thermal, chemical, and inflammatory pain. TRPV1s are expressed in some dorsal horn (DH) neurons, but their contribution, if any, to central pain processing still remains unclear. We studied the effects of 2 μM capsaicin-induced TRPV1 activation in organotypically cultured substantia gelatinosa neurons from post-natal (8–12) mice. Capsaicin affected sIPSC frequency (272 ± 60% of control, n = 14, P < 0.02), but not amplitude (131 ± 12% of control, n = 14, P > 0.05) in patch clamp recordings, also in the presence of 50 μM AP-5 (frequency: 265 ± 69% of control; n = 8, P < 0.05; amplitude: 156 ± 28% of control; n = 8, P > 0.05). The frequency increase was reduced by TTX (181 ± 21% of control; n = 12, P < 0.05). Pre-administration of I-RTX (1 μM), a TRPV1 antagonist, prevented the capsaicin effect (frequency: 149 ± 28% of control, P > 0.05, n = 12; amplitude: 97 ± 4% of control, P > 0.05, n = 12). NADA (1 μM), an endovanilloid/endocannabinoid agonist of TRPV1, induced a significant increase of sISPC frequency (191 ± 40% of control; n = 8, P < 0.05) without affecting the amplitude (102 ± 6% of control; n = 8, P > 0.05), and the co-application of two naturally occurring N-acyldopamines, PALDA (5 μM) and STEARDA (5 μM) that facilitate the effect of TRPV1 agonists, also induced a significant increase of sIPSC frequency (278 ± 67% of control, n = 6, P < 0.05). The presence of TRPV1 protein and mRNA in DH neurons was confirmed by histological (immunocytochemistry, in situ PCR) and biochemical (Western blotting, PCR) procedures. These data show that TRPV1 modulates inhibitory neurotransmission in cultured substantia gelatinosa neurons, and suggest that endogenous agonists can activate the spinal receptors in vivo.     

TAOK3, a novel genome-wide association study locus associated with morphine requirement and postoperative pain in a retrospective pediatric day surgery population

Candidate gene studies have revealed limited genetic bases for opioid analgesic response variability. Genome-wide association studies facilitate impartial queries of common genetic variants, allowing identification of novel genetic contributions to drug effect. Illumina (Illumina Inc, San Diego, CA, USA) single nucleotide polymorphism (SNP) arrays were used to investigate SNP associations with total morphine requirement as a quantitative trait locus and with postoperative pain in a retrospective population of opioid-naïve children ages 4–18 years who had undergone day surgery tonsillectomy and adenoidectomy. In an independent replication cohort, significant genome-wide association studies-identified SNPs were assayed using TaqMan probes. Among 617 comprehensively phenotyped children, the 277 subjects of European Caucasian (EC) ancestry demonstrated nominal association between morphine dose and a series of novel SNPs (top rs795484, P = 1.01 × 10⁻⁶ and rs1277441, P = 2.77 × 10⁻⁶) at the TAOK3 locus. Age, body mass index, and physical status were included covariates. Morphine requirement averaged 132.4 μg/kg (SD 40.9). Each minor allele at rs795484 (guanine [G] > adenine [A]) contributed +17.6 μg/kg (95% confidence interval [CI] 10.7–24.4) to dose. Effect direction and magnitude were replicated in an independent cohort of 75 EC children (P < 0.05). No association with morphine dose was detected in African Americans (AA) (n = 241). Postoperative pain scores ?7/10 were associated with rs795484 (G > A) in the EC cohort (odds ratio 2.35, 95% CI 1.56-3.52, P < 0.00005) and this association replicated in AA children (odds ratio 1.76, 95% CI 1.14-2.71, P < 0.01). Variants in TAOK3 encoding the serine/threonine-protein kinase, TAO3, are associated with increased morphine requirement in children of EC ancestry and with increased acute postoperative pain in both EC and AA subjects.     

Intrathecal combination of ziconotide and morphine for refractory cancer pain: a rapidly acting and effective choice

Ziconotide is a nonopioid intrathecal analgesic drug used to manage moderate to severe chronic pain. The aim of this work is to assess the safety and efficacy of intrathecal (IT) combination of ziconotide and morphine in malignant pain refractory to high doses of oral opioids. Patients with malignant pain refractory to high oral opioids doses with a mean visual analogue scale of pain intensity (VASPI) score of ?70 mm were enrolled. An IT combination therapy was administered: Ziconotide was started at a dose of 2.4 μg/day, followed by increases of 1.2 μg/day at intervals of at least 7 days, and an initial IT daily dose of morphine was calculated based on its oral daily dose. Percentage change in VASPI scores from baseline was calculated at 2 days, at 7 days, and weekly until the first 28 days. The mean percentage change of VASPI score from baseline was used for efficacy assessment. Safety was monitored based on adverse events and routine laboratory values. Twenty patients were enrolled, with a mean daily VASPI score at rest of 90 ± 7. All had a disseminated cancer with bone metastases involving the spine. The percentage changes in VASPI mean scores from baseline to 2 days, 7 days, and 28 days were 39 ± 13% (95% confidence interval [CI] = 13.61-64.49, P < .001), 51 ± 12% (95% CI = 27.56-74.56, P < .001), and 62 ± 13% (95% CI = 36.03-87.89%, P < .001), respectively. Four patients experienced mild adverse events related to the study drugs. In conclusion, an IT combination of low doses of ziconotide and morphine allows safe and rapid control of oral opioid-refractory malignant pain.     

Nonsteroidal anti-inflammatory drugs (NSAIDs) in older people: Prescribing patterns according to pain prevalence and adherence to clinical guidelines

The evidence on the patterns of nonsteroidal anti-inflammatory drug (NSAID) use according to pain prevalence and clinical guidelines in older people is sparse. This cross-sectional study examined the patterns of NSAID use according to pain prevalence and concordance with clinical guideline recommendations for safe NSAID use in older people, in relation to duration of use, patterns of use, concomitant use of proton pump inhibitors (PPIs), and prevalence of specific drug interactions. Community-dwelling men (n = 1696) age ?70 years living in Sydney were studied. 8.2% (n = 139) of participants reported regular NSAID use compared with 2.9% (n = 50) reporting as-needed use. The mean treatment duration for regular NSAID use was 4.9 years, suggesting long-term rather than short-term use as recommended by the guidelines. Although guidelines recommend use of PPIs together with an NSAID, only 25.2% of regular NSAID users reported PPI use. Regular NSAID users were significantly more likely to report use of opioid analgesics (P < .0001) compared with nonregular users. In relation to pain prevalence, regular NSAID users were significantly more likely to report chronic pain (P < .0001), recent pain (P = .0001), and chronic intrusive pain (P < .0001) compared with nonregular users. The findings of this study indicate that NSAID prescribing practices do not align with clinical guidelines for safe use in older people. This difference between the guideline recommendations and what is happening in the real world should be explored further.