Category Archives: Dolor

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Comparison of cannabinoids with known analgesics using a novel high throughput zebrafish larval model of nociception.

Category : Dolor

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Comparison of cannabinoids with known analgesics using a novel high throughput zebrafish larval model of nociception.

Behav Brain Res. 2017 Sep 18;:

Authors: Ellis LD, Berrue F, Morash M, Achenbach JC, Hill J, McDougall JJ

Abstract
It has been established that both adult and larval zebrafish are capable of showing nociceptive responses to noxious stimuli; however, the use of larvae to test novel analgesics has not been fully explored. Zebrafish larvae represent a low-cost, high-throughput alternative to traditional mammalian models for the assessment of product efficacy during the initial stages of drug development. In the current study, a novel model of nociception using zebrafish larvae is described. During the recovery from an acute exposure to low levels of acetic acid, larvae display innate changes in behaviour that may be indicative of nociception. To assess the usefulness of this model for testing potential analgesics, three known synthetic pain medications were assessed (ibuprofen, acetaminophen and tramadol) along with three naturally occurring products (honokiol, tetrahydrocannabinol and cannabidiol). When the effect of each compound on both the acetic acid recovery and control activity was compared there appeared to be both similarities and differences between the compounds. One of the most interesting effects was found for cannabidiol which appeared to oppose the activity change during the recovery period of AA exposed larvae while having a nominal effect on control activity. This would appear to be in line with current research that has demonstrated the nociceptive properties of cannabidiol. Here we have provided a novel model that will complement existing zebrafish models and will expand on the potential use of zebrafish larvae for studying both nociception and new analgesics.

PMID: 28935439 [PubMed – as supplied by publisher]

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[Delta-9-tetrahydrocannabinol-cannabidiol in the treatment of spasticity in chronic spinal cord injury: a clinical experience].

Category : Dolor

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[Delta-9-tetrahydrocannabinol-cannabidiol in the treatment of spasticity in chronic spinal cord injury: a clinical experience].

Rev Neurol. 2017 Oct 01;65(7):295-302

Authors: Grao-Castellote C, Torralba-Collados F, Gonzalez LM, Giner-Pascual M

Abstract
INTRODUCTION: Spasticity in chronic spinal cord injury is a condition that can have negative repercussions on the patient’s quality of life. Its treatment is complex and sometimes the outcome is insufficient. Cannabinoids have recently been used in multiple sclerosis to successfully treat spasticity that is refractory to other therapies.
AIM: To quantify the clinical response of a group of patients with spastic chronic spinal cord injury to the orally administered drug delta-9-tetrahydrocannabinol-cannabidiol (Sativex ®) as medication for use in special situations.
PATIENTS AND METHODS: The research consists of a six-month observational study in patients with chronic spinal cord injuries with refractory spasticity. The variables collected were: modified Ashworth scale, Penn spasm frequency scale, Numeric Rating Scale, and Visual Analogue Scale for pain. Additionally, clinical variables and side effects of the treatment were also collected.
RESULTS: Fifteen patients took part in this study. A significant improvement was observed on three of the scales recorded: modified Ashworth scale (z = -2.97; p = 0.003), Penn spasm frequency scale (z = -2.76; p = 0.006) and Numeric Rating Scale (z = -3.21; p = 0.001). The use of the drug was withdrawn in two patients due to side effects.
CONCLUSIONS: Sativex can be considered an alternative in patients with spasticity associated with chronic spinal cord injury for whom other therapeutic measures have been insufficient. Further studies need to be conducted before the use of this drug can be recommended and so as to define a complete profile of its long-term side effects.

PMID: 28929471 [PubMed – in process]

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Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as Adjunctive Therapy in Advanced Cancer Patients With Chronic Uncontrolled Pain.

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Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as Adjunctive Therapy in Advanced Cancer Patients With Chronic Uncontrolled Pain.

J Pain Symptom Manage. 2017 Sep 15;:

Authors: Lichtman AH, Lux EA, McQuade R, Rossetti S, Sanchez R, Sun W, Wright S, Kornyeyeva E, Fallon MT

Abstract
CONTEXT: Prior phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.
OBJECTIVE: To assess adjunctive nabiximols (Sativex(®)), an extract of Cannabis sativa containing two potentially therapeutic cannabinoids (Δ9-tetrahydrocannabinol [27 mg/mL] and cannabidiol [25mg/mL]), in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.
METHODS: Phase 3, double-blind, randomized, placebo-controlled trial in patients with advanced cancer and average pain NRS scores ≥ 4 and ≤ 8 despite optimized opioid therapy. Patients randomized to nabiximols (n=199) or placebo (n=198) self-titrated study medications over a 2-week period, followed by a 3-week treatment period at the titrated dose.
RESULTS: Median percent improvements in average pain NRS score from baseline to end of treatment in the nabiximols and placebo groups were 10.7% versus 4.5% (p=0.0854) in the ITT population (primary variable) and 15.5% versus 6.3% (p=0.0378) in the Per Protocol population. Nabiximols was statistically superior to placebo on two of three quality-of-life instruments at week 3 and on all three at week 5. In exploratory post hoc analyses, US patients, but not patients from the rest of the world (ROW), experienced significant benefits from nabiximols on multiple secondary endpoints. Possible contributing factors to differences in nabiximols efficacy include: 1) the US participants received lower doses of opioids at baseline than the ROW; and 2) the subgroups had different distribution of cancer pain types, which may have been related to differences in pathophysiology of pain. The safety profile of nabiximols was consistent with earlier studies.
CONCLUSIONS: Although not superior to placebo on the primary efficacy endpoint, nabiximols had benefits on multiple secondary endpoints, particularly in US patients. Nabiximols might have utility in patients with advanced cancer who receive a lower opioid dose, such as individuals with early intolerance to opioid therapy.

PMID: 28923526 [PubMed – as supplied by publisher]

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Cannabis constituent synergy in a mouse neuropathic pain model.

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Cannabis constituent synergy in a mouse neuropathic pain model.

Pain. 2017 Sep 01;:

Authors: Casey SL, Atwal N, Vaughan CW

Abstract
Cannabis and its psychoactive constituent Δ9-tetrahydrocannabinol (THC) have efficacy against neuropathic pain however, this is hampered by their side-effects. It has been suggested that co-administration with another major constituent cannabidiol (CBD) might enhance the analgesic actions of THC and minimise its deleterious side-effects. We examined the basis for this phytocannabinoid interaction in a mouse chronic constriction injury (CCI) model of neuropathic pain. Acute systemic administration of THC dose-dependently reduced CCI-induced mechanical and cold allodynia, but also produced motor incoordination, catalepsy and sedation. CBD produced a lesser dose-dependent reduction in allodynia, but did not produce the cannabinoid side-effects. When co-administered in a fixed ratio, THC and CBD produced a biphasic dose-dependent reduction in allodynia. At low doses, the THC:CBD combination displayed a 200-fold increase in anti-allodynic potency, but had lower efficacy compared to that predicted for an additive drug interaction. By contrast, high THC:CBD doses had lower potency, but greater anti-allodynic efficacy compared to that predicted for an additive interaction. Only the high dose THC:CBD anti-allodynia was associated with cannabinoid side-effects and these were similar to those of THC alone. Unlike THC, the low dose THC:CBD anti-allodynia was not cannabinoid receptor mediated. These findings demonstrate that CBD synergistically enhances the pain relieving actions of THC in an animal neuropathic pain model, but has little impact on the THC-induced side-effects. This suggests that low dose THC:CBD combination treatment has potential in the treatment of neuropathic pain.

PMID: 28885457 [PubMed – as supplied by publisher]

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Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.

Category : Dolor

Attenuation of early phase inflammation by cannabidiol prevents pain and nerve damage in rat osteoarthritis.

Pain. 2017 Sep 01;:

Authors: Philpott HT, O’Brien M, McDougall JJ

Abstract
Osteoarthritis (OA) is a multifactorial joint disease, which includes joint degeneration, intermittent inflammation, and peripheral neuropathy. Cannabidiol (CBD) is a non-euphoria producing constituent of cannabis that has the potential to relieve pain. The aim of this study was to determine if CBD is anti-nociceptive in OA, and whether inhibition of inflammation by CBD could prevent the development of OA pain and joint neuropathy. OA was induced in male Wistar rats (150-175g) by intra-articular injection of sodium monoiodoacetate (MIA; 3mg). On day 14 (end stage OA), joint afferent mechanosensitivity was assessed using in vivo electrophysiology while pain behaviour was measured by von Frey hair algesiometry and dynamic incapacitance. To investigate acute joint inflammation, blood flow and leukocyte trafficking were measured on day 1 post-MIA. Joint nerve myelination was calculated by G-ratio analysis. The therapeutic and prophylactic effects of peripheral CBD (100-300μg) were assessed. In end stage OA, CBD dose-dependently decreased joint afferent firing rate, and increased withdrawal threshold and weight bearing (p<0.0001; n=8). Acute, transient joint inflammation was reduced by local CBD treatment (p<0.0001; n=6). Prophylactic administration of CBD prevented the development of MIA-induced joint pain at later time points (p<0.0001; n=8), and was also found to be neuroprotective (p<0.05; n=6-8). The data presented here indicate that local administration of CBD blocked OA pain. Prophylactic CBD treatment prevented the later development of pain and nerve damage in these OA joints. These findings suggest that CBD may be a safe, useful therapeutic for treating OA joint neuropathic pain.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

PMID: 28885454 [PubMed – as supplied by publisher]

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A randomised controlled cross-over double-blind pilot study protocol on THC:CBD oromucosal spray efficacy as an add-on therapy for post-stroke spasticity.

Category : Dolor

A randomised controlled cross-over double-blind pilot study protocol on THC:CBD oromucosal spray efficacy as an add-on therapy for post-stroke spasticity.

BMJ Open. 2017 Sep 07;7(9):e016843

Authors: Marinelli L, Balestrino M, Mori L, Puce L, Rosa GM, Giorello L, Currà A, Fattapposta F, Serrati C, Gandolfo C, Abbruzzese G, Trompetto C

Abstract
INTRODUCTION: Stroke is the most disabling neurological disorder and often causes spasticity. Transmucosal cannabinoids (tetrahydrocannabinol and cannabidiol (THC:CBD), Sativex) is currently available to treat spasticity-associated symptoms in patients with multiple sclerosis. Cannabinoids are being considered useful also in the treatment of pain, nausea and epilepsy, but may bear and increased risk for cardiovascular events. Spasticity is often assessed with subjective and clinical rating scales, which are unable to measure the increased excitability of the monosynaptic reflex, considered the hallmark of spasticity. The neurophysiological assessment of the stretch reflex provides a precise and objective method to measure spasticity. We propose a novel study to understand if Sativex could be useful in reducing spasticity in stroke survivors and investigating tolerability and safety by accurate cardiovascular monitoring.
METHODS AND ANALYSIS: We will recruit 50 patients with spasticity following stroke to take THC:CBD in a double-blind placebo-controlled cross-over study. Spasticity will be assessed with a numeric rating scale for spasticity, the modified Ashworth scale and with the electromyographical recording of the stretch reflex. The cardiovascular risk will be assessed prior to inclusion. Blood pressure, heart rate, number of daily spasms, bladder function, sleep disruption and adverse events will be monitored throughout the study. A mixed-model analysis of variance will be used to compare the stretch reflex amplitude between the time points; semiquantitative measures will be compared using the Mann-Whitney test (THC:CBD vs placebo) and Wilcoxon test (baseline vs treatment).
ETHICS AND DISSEMINATION: The study was registered on the EudraCT database with number 2016-001034-10 and approved by both the Italian Medicines Agency (Agenzia Italiana del Farmaco) and local Ethics Committee ‘Comitato Etico Regionale della Liguria’. Data will be made anonymous and uploaded to a open access repository. Results will be disseminated by presentations at national and international conferences and by publication in journals of clinical neuroscience and neurology.

PMID: 28882919 [PubMed – in process]

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A selective review of medical cannabis in cancer pain management.

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A selective review of medical cannabis in cancer pain management.

Ann Palliat Med. 2017 Aug 23;:

Authors: Blake A, Wan BA, Malek L, DeAngelis C, Diaz P, Lao N, Chow E, O’Hearn S

Abstract
Insufficient management of cancer-associated chronic and neuropathic pain adversely affects patient quality of life. Patients who do not respond well to opioid analgesics, or have severe side effects from the use of traditional analgesics are in need of alternative therapeutic op-tions. Anecdotal evidence suggests that medical cannabis has potential to effectively manage pain in this patient population. This review presents a selection of representative clinical studies, from small pilot studies conducted in 1975, to double-blind placebo-controlled trials conducted in 2014 that evaluated the efficacy of cannabinoid-based therapies containing tetrahydrocannabinol (THC) and cannabidiol (CBD) for reducing cancer-associated pain. A review of literature published on Medline between 1975 and 2017 identified five clinical studies that evaluated the effect of THC or CBD on controlling cancer pain, which have been reviewed and summarised. Five studies that evaluated THC oil capsules, THC:CBD oromucosal spray (nabiximols), or THC oromucosal sprays found some evidence of cancer pain reduction associated with these therapies. A variety of doses ranging from 2.7-43.2 mg/day THC and 0-40 mg/day CBD were administered. Higher doses of THC were correlated with increased pain relief in some studies. One study found that significant pain relief was achieved in doses as low as 2.7-10.8 mg THC in combination with 2.5-10.0 mg CBD, but there was conflicting evidence on whether higher doses provide superior pain relief. Some reported side effects include drowsiness, hypotension, mental clouding, and nausea and vomiting. There is evidence suggesting that medical cannabis reduces chronic or neu-ropathic pain in advanced cancer patients. However, the results of many studies lacked statistical power, in some cases due to limited number of study subjects. Therefore, there is a need for the conduct of further double-blind, placebo-controlled clinical trials with large sample sizes in order to establish the optimal dosage and efficacy of different cannabis-based therapies.

PMID: 28866904 [PubMed – as supplied by publisher]

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Cannabis and Pain: A Clinical Review.

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Cannabis and Pain: A Clinical Review.

Cannabis Cannabinoid Res. 2017;2(1):96-104

Authors: Hill KP, Palastro MD, Johnson B, Ditre JW

Abstract
Introduction: Cannabis has been used for medical purposes across the world for centuries. As states and countries implement medical and recreational cannabis policies, increasing numbers of people are using cannabis pharmacotherapy for pain. There is a theoretical rationale for cannabis’ efficacy for pain management, although the subjective pain relief from cannabis may not match objective measurements of analgesia. As more patients turn to cannabis for pain relief, there is a need for additional scientific evidence to evaluate this increase. Materials and Methods: Research for this review was performed in the PubMed/National Library of Medicine database. Discussion: Preclinical studies demonstrate a narrow therapeutic window for cannabis as pharmacotherapy for pain; the body of clinical evidence for this indication is not as extensive. A recent meta-analysis of clinical trials of cannabis and cannabinoids for pain found modest evidence supporting the use of cannabinoid pharmacotherapy for pain. Recent epidemiological studies have provided initial evidence for a possible reduction in opioid pharmacotherapy for pain as a result of increased implementation of medical cannabis regimens. Conclusion: With increased use of medical cannabis as pharmacotherapy for pain comes a need for comprehensive risk-benefit discussions that take into account cannabis’ significant possible side effects. As cannabis use increases in the context of medical and recreational cannabis policies, additional research to support or refute the current evidence base is essential to attempt to answer the questions that so many healthcare professionals and patients are asking.

PMID: 28861509 [PubMed]

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Training and Practices of Cannabis Dispensary Staff.

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Training and Practices of Cannabis Dispensary Staff.

Cannabis Cannabinoid Res. 2016;1(1):244-251

Authors: Haug NA, Kieschnick D, Sottile JE, Babson KA, Vandrey R, Bonn-Miller MO

Abstract
Introduction: The proliferation of cannabis dispensaries within the United States has emerged from patient demand for the legalization of cannabis as an alternative treatment for a number of conditions and symptoms. Unfortunately, nothing is known about the practices of dispensary staff with respect to recommendation of cannabis strains/concentrations for specific patient ailments. To address this limitation, the present study assessed the training and practices of cannabis dispensary staff. Materials and Methods: Medical and nonmedical dispensary staff (n=55) were recruited via e-mail and social media to complete an online survey assessing their demographic characteristics, dispensary features, patient characteristics, formal training, and cannabis recommendation practices. Results: Fifty-five percent of dispensary staff reported some formal training for their position, with 20% reporting medical/scientific training. A majority (94%) indicated that they provide specific cannabis advice to patients. In terms of strains, dispensary staff trended toward recommendations of Indica for anxiety, chronic pain, insomnia, nightmares, and Tourette’s syndrome. They were more likely to recommend Indica and hybrid plants for post-traumatic stress disorder (PTSD)/trauma and muscle spasms. In contrast, staff were less likely to recommend Indica for depression; hybrid strains were most often recommended for amyotrophic lateral sclerosis (ALS). In terms of cannabinoid concentrations, dispensary staff were most likely to recommend a 1:1 ratio of delta-9-tetrahydrocannabinol (THC):cannabidiol (CBD) for patients suffering from anxiety, Crohn’s disease, hepatitis C, and PTSD/trauma, while patients seeking appetite stimulation were most likely to be recommended THC. Staff recommended high CBD for arthritis and Alzheimer’s disease and a high CBD or 1:1 ratio for ALS, epilepsy, and muscle spasms. Conclusions: Although many dispensary staff are making recommendations consistent with current evidence, some are recommending cannabis that has either not been shown effective for, or could exacerbate, a patient’s condition. Findings underscore the importance of consistent, evidence-based, training of dispensary staff who provide specific recommendations for patient medical conditions.

PMID: 28861496 [PubMed]

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Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.

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Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.

Adv Pharmacol. 2017;80:67-134

Authors: Russo EB, Marcu J

Abstract
The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam’s professed “pharmacological treasure trove.”

PMID: 28826544 [PubMed – in process]

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