Archive for the ‘Pain’ Category

Historically and anecdotally cannabinoids have been used as analgesic agents. In recent years, there has been an escalating interest in developing cannabis-derived medications to treat severe pain. This review provides an overview of the history of cannabis use in medicine, cannabinoid signaling pathways, and current data from preclinical as well as clinical studies on using cannabinoids as potential analgesic agents. Clinical and experimental studies show that cannabis-derived compounds act as antiemetic, appetite modulating, and analgesic agents. However, the efficacy of individual products is variable and dependent upon the route of administration. As opioids are the only therapy for severe pain, analgesic ability of cannabinoids may provide a much-needed alternative to opioids. Moreover, cannabinoids act synergistically with opioids and act as opioid sparing agents, allowing lower doses and fewer side effects from chronic opioid therapy. Thus, rational use of cannabis-based medications deserves serious consideration to alleviate the suffering of patients due to severe pain.

The therapeutic potential of cannabinoids has been the topic of extensive investigation following the discovery of cannabinoid receptors and their endogenous ligands. Cannabinoid receptors and their endogenous ligands are present at supraspinal, spinal and peripheral levels. Cannabinoids suppress behavioral responses to noxious stimulation and suppress nociceptive processing through activation of cannabinoid CB(1) and CB(2) receptor subtypes. Endocannabinoids, the brain’s own cannabis-like substances, share the same molecular target as Delta(9)-tetrahydrocannabinol, the main psychoactive component in cannabis. Endocannabinoids serve as synaptic circuit breakers and regulate multiple physiological and pathological conditions, e.g. regulation of food intake, immunomodulation, inflammation, analgesia, cancer, addictive behavior, epilepsy and others. This review will focus on uncovering the roles of anandamide and 2-arachidonoylglycerol, the two best characterized endocannabinoids identified to date, in controlling nociceptive responding. The roles of anandamide and 2-arachidonoylglycerol, released under physiological conditions, in modulating nociceptive responding at different levels of the neuraxis will be emphasized in this review. Effects of modulation of endocannabinoid levels through inhibition of endocannabinoid hydrolysis and uptake is also compared with effects of exogenous administration of synthetic endocannabinoids in acute, inflammatory and neuropathic pain models. Finally, the therapeutic potential of the endocannabinoid signaling system is discussed in the context of identifying novel pharmacotherapies for the treatment of pain.

Anandamide, an endocannabinoid, is degraded by the enzyme fatty acid amide hydrolase which can be inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). The present work was designed to study the peripheral interactions between anandamide and ibuprofen (a non-specific cyclooxygenase inhibitor) in the rat formalin test. We first determined the ED₅₀ for anandamide (0.018 μg ± 0.009), ibuprofen (0.18 μg ± 0.09), and their combination (0.006 μg ± 0.002). Drugs were given 15 min before a 2.5% formalin injection into the dorsal surface of the right hind paw. Results were analyzed using isobolographic analysis. The antinociceptive interaction between anandamide and ibuprofen was synergistic. To further investigate the mechanisms by which the combination of anandamide with ibuprofen produced their antinociceptive effects, we used specific antagonists for the cannabinoid CB₁ (AM251; 80 μg) and CB₂ (AM630; 25 μg) receptors. We demonstrated that the antinociceptive effects of ibuprofen were not antagonized by either AM251 or AM630 and that those of anandamide were antagonized by AM251 but not by AM630. The synergistic antinociceptive effects of the combination of anandamide with ibuprofen were completely antagonized by AM251 but only partially inhibited by AM630. In conclusion, locally (hind paw) injected anandamide, ibuprofen or combination thereof decreased pain behavior in the formalin test. The combination of anandamide with ibuprofen produced synergistic antinociceptive effects involving both cannabinoid CB₁ and CB₂ receptors. Comprehension of the mechanisms involved needs further investigation.

The endocannabinoids occurring naturally in the human body are closely related to the active ingredients of the cannabis plant. Cannabis has been used for thousands of years, for example to treat chronic pain. However, the fact that the endocannabinoids produced by the body itself can also be involved in the origin of pain is the astonishing result of studies by a Zurich research team.

The first mention of cannabis as a medicinal plant was in the Chinese book of medicinal plants “Shennong bencao jing”, which is almost 5000 years old. The Chinese emperor Shennong is said to have recommended cannabis resin as a remedy for various illnesses. After the use of its active ingredients for thousands of years to alleviate chronic pain, a study by the research group led by Hanns Ulrich Zeilhofer, Professor at the Institute of Pharmaceutical Sciences at ETH Zurich and the Institute of Pharmacology and Toxicology at the University of Zurich now shows that the endocannabinoids produced by the body itself can lead to pain sensitisation in certain types of pain. Their study was recently published in the scientific journal Science.

Short-circuit in the spinal cord

Pain and touch are conducted to the brain through the spinal cord via two different systems. This enables the brain to distinguish between pain and simple touch. However, because the two systems are interconnected via nerve fibres in the spinal cord, simple touches can also be perceived as pain, for example as a result of a “short circuit”. Such faulty circuits can occur if inhibitory chemical messengers (neurotransmitters) in the spinal cord are absent or blocked. Zeilhofer says, “This happens in various illnesses and can even be triggered by intense pain stimuli themselves.”

The body’s own endocannabinoids play a considerable part in the biochemical processes taking place in this, as the study by Zeilhofer and his team shows. In particular, the release of endocannabinoids in the spinal cord seems to be responsible for the fact that, after an initial pain stimulus, pain sensitivity spreads beyond the area originally stimulated. Even slight touch in this area is then perceived as painful. The endocannabinoids thus cause a “short circuit” between the touch signals and pain.

The scientists tested the theory that endocannabinoids released in the spinal cord during intense pain stimuli are responsible for this short-circuit. It actually became apparent that activating the endocannabinoid receptors on isolated spinal cord reduced the release of pain-inhibiting neurotransmitters. Animals that had developed the expected oversensitivity to slight touching after a pain stimulus behaved normally again after their cannabinoid receptors in the spinal cord were blocked.

Endocannabinoid inhibitors relieve pain

The fact that these processes also occur in humans was shown by experiments on healthy volunteers carried out in the Anaesthesiology Department at the University of Erlangen. Pain receptors in the volunteers’ skin were locally stimulated with an electric current, after which the size of the area hypersensitive to pain was determined. In the next step, half of the volunteers received a placebo for ten days, while the others were given Rimonabant, a substance that blocks certain cannabinoid receptors. The experiment was then repeated. Zeilhofer says, “The painful area formed in the test subjects whose endocannabinoid receptors had been blocked was about fifty percent smaller than in those who had taken the placebo.”

Helpful to the pharmaceutical industry

However, further experiments also showed that other forms of pain, e.g. those occurring as a result of nerve injuries, developed normally in mice that lacked endocannabinoid receptors. The endocannabinoids seem to play no major pain promoting role in this case. Zeilhofer says, “In the next step we want to find out which pain patients might possibly benefit from blocking the cannabinoid receptors. At any rate our findings should be of great interest to drug companies who are working with this pain model to develop new analgesics.”

OBJECTIVES: This study was conducted to better understand the characteristics of chronic pain patients seeking treatment with medicinal cannabis (MC).
DESIGN: Retrospective chart reviews of 139 patients (87 males, median age 47 years; 52 females, median age 48 years); all were legally qualified for MC use in Washington State.
SETTING: Regional pain clinic staffed by university faculty.
PARTICIPANTS: Inclusion criteria: age 18 years and older; having legally accessed MC treatment, with valid documentation in their medical records. All data were de-identified.
MAIN OUTCOME MEASURES: Records were scored for multiple indicators, including time since initial MC authorization, qualifying condition(s), McGill Pain score, functional status, use of other analgesic modalities, including opioids, and patterns of use over time.
RESULTS: Of 139 patients, 15 (11 percent) had prior authorizations for MC before seeking care in this clinic. The sample contained 236.4 patient-years of authorized MC use. Time of authorized use ranged from 11 days to 8.31 years (median of 1.12 years). Most patients were male (63 percent) yet female patients averaged 0.18 years longer authorized use. There were no other gender-specific trends or factors. Most patients (n = 123, 88 percent) had more than one pain syndrome present. Myofascial pain syndrome was the most common diagnosis (n = 114, 82 percent), followed by neuropathic pain (n = 89, 64 percent), discogenic back pain (n = 72, 51.7 percent), and osteoarthritis (n = 37, 26.6 percent). Other diagnoses included diabetic neuropathy, central pain syndrome, phantom pain, spinal cord injury, fibromyalgia, rheumatoid arthritis, HIV neuropathy, visceral pain, and malignant pain. In 51 (37 percent) patients, there were documented instances of major hurdles related to accessing MC, including prior physicians unwilling to authorize use, legal problems related to MC use, and difficulties in finding an affordable and consistent supply of MC.
CONCLUSIONS: Data indicate that males and females access MC at approximately the same rate, with similar median authorization times. Although the majority of patient records documented significant symptom alleviation with MC, major treatment access and delivery barriers remain.

BACKGROUND: Postherpetic neuralgia is a frequent adverse event in herpes zoster patients and difficult to treat. Conventional analgetic therapy often fails to reduce the burning pain transmitted by unmyelinated nerve fibers. These nerves express cannabinoid receptors which exert a role in modulation of nociceptive symptoms. Therefore, topical therapy with cannabinoid receptor agonist seems likely to suppress local burning pain. PATIENTS AND METHODS: In an open-labeled trial, 8 patients with facial postherpetic neuralgia received a cream containing the cannabinoid receptor agonist N-palmitoylethanolamine. The course of symptoms was scored with the visual analog scale. RESULTS: 5 of 8 patients (62.5 %) experienced a mean pain reduction of 87.8 %. Therapy was tolerated by all patients. No unpleasant sensations or adverse events occurred. CONCLUSIONS: Topical cannabinoid receptor agonists are an effective and well-tolerated adjuvant therapy option in postherpetic neuralgia.