Treatment response and central pain processing in Anterior Cutaneous Nerve Entrapment Syndrome: An explorative study.

BACKGROUND: 10-30% of chronic abdominal pain originates in the abdominal wall. A common cause for chronic abdominal wall pain is the Anterior Cutaneous Nerve Entrapment Syndrome (ACNES), in which an intercostal nerve branch is entrapped in the abdominal rectus sheath. Treatment consists of local anaesthetics and neurectomy, and is ineffective in 25% of cases for yet unknown reasons. In some conditions, chronic pain is the result of altered pain processing. This so-called sensitization can manifest as segmental or even generalized hyperalgesia, and is generally difficult to treat. OBJECTIVE: The aim of this study was to assess pain processing in ACNES patients responsive and refractory to treatment by using Quantitative Sensory Testing, in order to explore whether signs of altered central pain processing are present in ACNES and are a possible explanation for poor treatment outcomes. METHODS: 50 patients treated for ACNES with locally orientated treatment were included. They were allocated to a responsive or refractory group based on their response to treatment. Patients showing an improvement of the Visual Analogue Scale (VAS) pain score combined with a current absolute VAS of <40mm were scored as responsive. Sensation and pain thresholds to pressure and electric skin stimulation were determined in the paravertebral bilateral ACNES dermatomes and at four control areas on the non-dominant side of the body, i.e. the musculus trapezius pars medialis, musculus rectus femoris, musculus abductor hallucis and the thenar. The ACNES dermatomes were chosen to signal segmental hyperalgesia and the sum of the control areas together as a reflection of generalized hyperalgesia. Lower thresholds were interpreted as signs of sensitized pain processing. To test for alterations in endogenous pain inhibition, a conditioned pain modulation (CPM) response to a cold pressor task was determined. Also, patients filled in three pain-related questionnaires, to evaluate possible influence of psychological characteristics on the experienced pain. RESULTS: Patients refractory to treatment showed significantly lower pressure pain thresholds in the ACNES dermatomes and for the sum of as well as in two individual control areas. No differences were found between groups for electric thresholds or CPM response. Duration of complaints before diagnosis and treatment was significantly longer in the refractory compared to the responsive group, and refractory patients scored higher on the pain-related psychological surveys. CONCLUSION AND IMPLICATIONS: In this hypothesis-generating exploratory study, ACNES patients refractory to treatment showed more signs of sensitized segmental and central pain processing. A longer duration of complaints before diagnosis and treatment may be related to these alterations in pain processing, and both findings could be associated with less effective locally orientated treatment. In order to validate these hypotheses further research is needed. REGISTRATION NUMBER: NCT01920880 (Clinical Trials Register; http://www.clinicaltrials.gov).

Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study.

BACKGROUND & AIMS: Delta-9-tetrahydrocannabinol (THC) is the most abundant cannabinoid from the plant Cannabis sativa. There is only equivocal evidence that THC has analgesic effects. We performed a phase 2 controlled trial to evaluate the analgesic efficacy, pharmacokinetics, safety, and tolerability of an oral tablet containing purified THC in patients with chronic abdominal pain. METHODS: Sixty-five patients with chronic abdominal pain for 3 months or more (numeric rating scale scores of 3 or more) after surgery or because of chronic pancreatitis were randomly assigned to groups given the THC tablet or identical matching placebos for 50-52 days. Subjects in the THC group were given the tablet first in a step-up phase (3 mg 3 times daily for 5 days and then 5 mg 3 times daily for 5 days), followed by a stable dose phase (8 mg 3 times daily until days 50-52). Preceding and during the entire study period, patients were asked to continue taking their medications (including analgesics) according to prescription. Patients reported any additional pain medications in a diary. Efficacy and safety assessments were conducted preceding medication intake (day 1), after 15 days, and at 50-52 days. Plasma samples were collected on study days 1, 15, and 50-52; mean plasma concentration curves of THC and 11-OH-THC were plotted. The primary end point was pain relief, which was measured by a visual analogue scale (VAS) of the mean pain (VAS mean scores) on the basis of information from patient diaries. Secondary end points included pain and quality of life (determined from patient questionnaires), pharmacokinetics, and safety. RESULTS: At days 50-52, VAS mean scores did not differ significantly between the THC and placebo groups (F1,46 = 0.016; P = .901). Between the start and end of the study, VAS mean scores decreased by 1.6 points (40%) in the THC group compared with 1.9 points (37%) in the placebo group. No differences were observed in secondary outcomes. Oral THC was generally well-absorbed. Seven patients in the THC group stopped taking the tablets because of adverse events, compared with 2 patients in the placebo group. All (possibly) related adverse events were mild or moderate. CONCLUSIONS: In a phase 2 study, we found no difference between a THC tablet and a placebo tablet in reducing pain measures in patients with chronic abdominal pain. THC, administered 3 times daily, was safe and well-tolerated during a 50-day to 52-day treatment period. ClinicalTrials.gov number: NCT01562483 and NCT01551511.

Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability.

AIM: We aimed to assess the analgesic efficacy, pharmacokinetics, tolerability and safety of a single dose of Δ9-THC in patients with chronic abdominal pain resulting from chronic pancreatitis (CP). METHODS: This was a randomized, single dose, double-blinded, placebo-controlled, two way crossover study in patients suffering from abdominal pain as result of CP (n = 24), post hoc subdivided into opioid and non-opioid users. Δ9-THC (8 mg) or active placebo (5 mg/10 mg diazepam) was administered orally in a double dummy design. RESULTS: No treatment effect was shown for delta VAS pain scores after Δ9-THC compared with diazepam. Δ9-THC was well absorbed with a mean tmax of 123 min. No significant differences were found between Δ9-THC vs. diazepam for alertness, mood, calmness or balance. Feeling anxious and heart rate were significantly increased after Δ9-THC compared with diazepam. The most frequently reported adverse events (AEs) after Δ9-THC administration were somnolence, dry mouth, dizziness and euphoric mood. CONCLUSIONS: A single dose of Δ9-THC was not efficacious in reducing chronic pain resulting from CP, but was well tolerated with only mild or moderate AEs. The PK results in CP patients showed delayed absorption and an increased variability compared with healthy volunteers.

Risk factors for chronic postsurgical abdominal and pelvic pain.

Chronic postsurgical pain (CPSP) may develop after any surgical procedure, and is a common feature after abdominal and pelvic surgery with a prevalence varying between 10 and 40%. The pathological mechanisms leading to chronic CPSP are probably inflammation, tissue and nerve damage and alterations in central pain processing. The mechanisms in chronic postsurgical abdominal and pelvic pain are poorly studied and research has largely focused on reporting of prevalence and describing risk factors, including patient characteristics, psychological factors, surgical procedure and pre- and acute postoperative pain. In this review, the most important risk factors are discussed, and aiming for preventive, personalized health care, possible methods for prediction of susceptibility and potential strategies for diminishing chronic postsurgical abdominal and pelvic pain are provided.

Dronabinol and chronic pain: importance of mechanistic considerations.

INTRODUCTION: Although medicinal cannabis has been used for many centuries, the therapeutic potential of delta-9-tetrahydrocannabinol (Δ9-THC; international non-proprietary name = dronabinol) in current pain management remains unclear. Several pharmaceutical products with defined natural or synthesized Δ9-THC content have been developed, resulting in increasing numbers of clinical trials investigating the analgesic efficacy of dronabinol in various pain conditions. Different underlying pain mechanisms, including sensitization of nociceptive sensory pathways and alterations in cognitive and autonomic processing, might explain the varying analgesic effects of dronabinol in chronic pain states. AREAS COVERED: The pharmacokinetics, pharmacodynamics and mechanisms of action of products with a defined dronabinol content are summarized. Additionally, randomized clinical trials investigating the analgesic efficacy of pharmaceutical cannabis based products are reviewed for the treatment of chronic nonmalignant pain. EXPERT OPINION: We suggest a mechanism-based approach beyond measurement of subjective pain relief to evaluate the therapeutic potential of dronabinol in chronic pain management. Development of objective mechanistic diagnostic biomarkers reflecting altered sensory and cognitive processing in the brain is essential to evaluate dronabinol induced analgesia, and to permit identification of responders and/or non-responders to dronabinol treatment.