The role of cannabinoids in pain control: the good, the bad, and the ugly.

Cannabinoids appear to possess many potential medical uses, which may extend to pain control. A narrative review of the literature has found a variety of studies testing botanical and synthetic cannabinoids in different pain syndromes (acute pain, cancer pain, chronic noncancer pain, fibromyalgia pain, migraine, neuropathic pain, visceral pain, and others). Results from these studies are mixed; cannabinoids appear to be most effective in controlling neuropathic pain, allodynia, medication-rebound headache, and chronic noncancer pain, but do not seem to offer any advantage over nonopioid analgesics for acute pain. Cannabinoids seem to work no better than placebo for visceral pain and conferred only modest analgesic effect in cancer pain. Cannabinoids do many good things - they appear to be effective in treating certain types of pain without the issues of tolerance associated with opioids. Negatively, marijuana currently has a very murky legal status all over the world - laws regulating its use are inconsistent and in flux. Thus, both patients and prescribers may be unsure about whether or not it is an appropriate form of pain control. Cannabinoid-based analgesia has been linked to potential memory deficits and cognitive impairment. A great deal more remains to be elucidated about cannabinoids which may emerge to play an important role in the treatment of neuropathic and possibly other painful conditions. There remains a great deal more to learn about the role of cannabinoids in pain management.

Concise review of the management of iatrogenic emesis using cannabinoids: emphasis on nabilone for chemotherapy-induced nausea and vomiting.

Chemotherapy-induced nausea and vomiting (CINV) is a prevalent, distressing, and burdensome side effect of cancer chemotherapy. It is estimated to affect the majority of patients receiving certain anti-cancer drug regimens and can be treatment-limiting, even for life-saving medications. Despite seemingly numerous options, such as antimuscarinic anticholinergics, antihistamines, 5-HT3 receptor antagonists, dopamine receptor antagonists, and neurokinin-1 receptor antagonists, preventative therapies are often inadequately effective, particularly for "delayed CINV"-leaving an important unmet clinical need. Cannabinoid receptor agonists, by virtue of their unique mechanism of action and efficacy and safety data reported in clinical trials, appear to offer a useful additional option. The mechanistic value of cannabinoids has been well known for many years, but these agents may have been underutilized in the past because of the notoriety and legal status of marijuana. While botanical marijuana contains nearly 500 components, including the psychoactive tetrahydrocannabinol (THC), nabilone is an established, single-entity synthetic cannabinoid receptor agonist that has become the focus of renewed interest. We review the basic pharmacology and clinical trial data of nabilone for use in prophylaxis and treatment of CINV.

Long-term use of opioids in 210 officially registered patients with chronic noncancer pain in Taiwan: A cross-sectional study.

BACKGROUND/PURPOSE: Prescribing opioids for chronic noncancer pain has been strictly regulated for two decades in Taiwan. The aim of this study was to survey the patients' perspectives and potential drawbacks following long-term use of opioids. METHODS: An observational cross-sectional survey using the Taiwanese version of Brief Pain Inventory was conducted among outpatients with chronic noncancer pain registered by the Taiwan Food and Drug Administration. Patients were also asked about their sexual behavior, depression, opioid misuse behaviors, and use of complementary and alternative medicine. RESULTS: For 210 of 328 outpatients (64.0%), the median pain duration was 96 months and opioid treatment duration was 57 months. The median morphine equivalent dose was 150 mg/d, with 30.5% of patients exceeding the daily watchful dose, defined as 200 mg of morphine equivalent dose. Pain reduction after taking opioids was ∼50% in the past week. The top three diagnoses were chronic pancreatitis, spinal cord injury, and neuralgia. The leading side effects were constipation (46.7%), and decreased sexual desire (69.5%) and satisfaction (57.9%). Depression was currently diagnosed in 55.2% of patients. Twenty patients (9.5%) displayed at least one aberrant behavior in the past month. Only 76 (36.2%) patients had ever received nerve block procedures, and 118 (56.2%) tried complementary and alternative medicine. CONCLUSION: This nationwide survey described the concurrent pain intensity, daily function, and various adverse effects by long-term opioids among 210 monitored outpatients with chronic noncancer pain in Taiwan. More efforts are suggested to reduce opioid prescriptions in the 30% of patients exceeding daily watchful dose.

Planarians in pharmacology: parthenolide is a specific behavioral antagonist of cocaine in the planarian Girardia tigrina.

Planarians are traditional animal models in developmental and regeneration biology. Recently, these organisms are arising as vertebrate-relevant animal models in neuropharmacology. Using an adaptation of published behavioral protocols, we have described the alleviation of cocaine-induced planarian seizure-like movements (pSLM) by a naturally-occurring sesquiterpene lactone, parthenolide. Interestingly, parthenolide does not prevent the expression of pSLM induced by amphetamines; in vertebrates, amphetamines interact with the same protein target as cocaine. Parthenolide is also unable to prevent pSLM elicited by the cholinergic com-pounds nicotine and cytisine or by the glutamatergic agents L- or D- glutamic acid or NMDA. Thus, we conclude that parthenolide is a specific anti-cocaine agent in this experimental organism.

Fixed-dose combinations for emerging treatment of pain.

INTRODUCTION: Pain is a large and growing medical need that is not currently being fully met, primarily due to the shortcomings of existing analgesics (insufficient efficacy or limiting side-effects). Better outcomes might be achieved using a combination of analgesics. The ratio of the combinations matters and should therefore be evaluated using rigorous quantitative and well-documented analysis. AREAS COVERED: Advances have been made in understanding the normal physiology of pain processing, including the pathways and neurotransmitters involved. Insight has also been gained about physiological processes that can lead to different 'types' of pain and the transition from acute to chronic pain conditions. This 'multimechanistic' nature of most pains is better matched using a 'multimechanistic' rather than 'monomechanistic' analgesic approach. Such an approach - and the experimental design and data analysis to assess optimal combinations - is described and discussed. EXPERT OPINION: There are sound pharmacologic, as well as practical, reasons for using combinations of drugs to treat pain. Compared with single agents, they offer a potential better match to the underlying pain physiology and thus greater efficacy or reduced side effects. The optimal efficacy and side-effect ratio must be determined in a scientifically rigorous manner.

A randomized, double-blind comparison shows the addition of oxygenated glycerol triesters to topical mentholated cream for the treatment of acute musculoskeletal pain demonstrates incremental benefit over time.

BACKGROUND: Topical analgesics are important products in the armamentarium for pain relief. METHODS AND FINDINGS: This study compared a topical analgesic product containing menthol to the same product with the addition of oxygenated glycerol triesters (OGTs) (also called essential oxygen oil) in 66 healthy adult subjects with acute musculoskeletal pain. Patients were randomized in a single-center, double-blind study to receive mentholated cream (MC) only or MC containing OGTs. Patients self-reported their pain intensity, lifestyle limitations, and evaluation of the mobility of the painful joint or muscle at baseline and three times daily over a seven-day course on a 100-mm visual analog scale (VAS). Patients in both groups experienced statistically significant pain relief on Day 8 over baseline, with the MC plus OGT-treated group reporting statistically significantly greater pain relief than the MC group (P = 0.016). In addition, patients treated with the combination product experienced an incremental decrease in pain during each of the 7 days of treatment in addition, and they had lower VAS scores and greater lifestyle and mobility improvements than the MC group. Both products were well tolerated with no serious adverse events reported and no signs of significant skin reactions in either group. CONCLUSION: Based on this study, a MC containing OGTs is safe, effective, and provided significantly better pain relief than MC alone. The combination of oxygenated glycerol trimesters and MC provided significant pain relief and offered continued improvement in pain relief over time.

Diselenium, instead of disulfide, bonded analogs of conotoxins: novel synthesis and pharmacotherapeutic potential.

The venoms of the cone snail (Conus) contain toxic peptides (conotoxins) that have remarkable selectivity for subtypes of a variety of mammalian voltage- and ligand-gated ion channels, G protein-coupled receptors, and neurotransmitter transporters. They thus have tremendous potential as pharmacologic tools. Less toxic analogs or mimetics could be highly-selective pharmacotherapeutic agents at their target sites. For this reason, conopeptides have been extensively studied and have progressed to clinical trials and even regulatory approval. However, the synthesis of the peptides remains difficult and stability and toxicity remain problems. A novel synthesis and testing of analogs incorporating diselenium bonds between selenocysteine residues in place of disulfide bonds between cysteine residues has recently been reported. The technique results in analogs that retain the folding of the native peptides, are more potent, and have the same or greater biological activity.

Preliminary observations of a novel topical oil with analgesic properties for treatment of acute and chronic pain syndromes.

OBJECTIVE: Essential oxygen oil (OxyRub from CreoMed Inc., Naples, FL, U.S.A.) is a novel topical analgesic currently commercially available in Europe and now available in the U.S.A. It represents an important alternative to other treatments (nonsteroidal anti-inflammatory drugs, acetaminophen, menthol, camphor) for managing mild to moderate acute and chronic pain. Several clinical trials of this oil will be reviewed. RESULTS: One large (n = 455) open-label trial found essential oxygen oil to be a safe and effective analgesic for a broad range of patients with acute and chronic pain. In that study, 80% of patients reported that their pain decreased by more than 75%. A double-blind placebo-controlled study (n = 50) found significant pain reduction for tendonitis in patients using essential oxygen oil. Another trial of essential oxygen oil vs. placebo (n = 50) with various pain diagnoses found that 98% of patients with various pain diagnoses reported "very good" pain relief in the oil group compared to 48% in the placebo group. Furthermore, a randomized controlled trial in 10 women to measure oxygen microcirculatory effect in the skin showed an increased microcirculatory effect with improved oxygenation (increased partial pressure of oxygen in the skin) after application of essential oxygen oil. In all studies, the oil was well tolerated. None of these studies has been previously published. CONCLUSIONS: Based on studies completed, essential oxygen oil has shown itself to be safe, has demonstrated positive analgesic effects for the treatment of acute and chronic pain, and has improved oxygen content in the skin as well as other dermatological parameters.

On deriving the dose-effect relation of an unknown second component: an example using buprenorphine preclinical data.

Buprenorphine, like many other drugs, displays a biphasic dose-response relation ('hormesis'), viz., its antinociceptive effect in some preclinical models increases up to some dose level (often achieving 100% effect) and decreases at high-doses. A decreasing component was evident in the tail-flick tests described here, occurring in both the mouse and the rat. While the mechanism of dose-related decline in antinociceptive effect, when observed, might be related to nociceptin/orphanin-FQ, the precise mechanism remains unknown. Regardless of the mechanism, the values of this dose-related decline yield data that can be used to calculate the dose-effect relation of the decreasing (unknown second) component. The calculation, which uses the same concept of dose equivalence that underlies additivity in isobolographic analysis, was employed here from tail-flick data obtained in mouse and rat. The derived dose-effect curves of the second component, though differing in efficacy between mouse and rat, displayed a very notable similarity. This novel technique offers possible insight into the dual low-dose (analgesic), high-dose (addiction medication) uses of buprenorphine.

Effects of chemotherapeutic agents 5-fluorouracil and methotrexate alone and combined in a mouse model of learning and memory.

RATIONALE: The concern that adjuvant cancer chemotherapy agents cause cognitive impairment in a significant number of patients has been expressed by patients and healthcare providers, but clinical studies have yielded conflicting results to date. OBJECTIVE: We directly tested two commonly used chemotherapeutic agents in a mouse model of learning and memory. MATERIALS AND METHODS: In the present study, mice were conditioned to respond for a liquid reinforcer (Ensure solution) in the presence of an audible tone on day 1 as a measure of acquisition and were then required to perform the same response on day 2 as a measure of retrieval and retention. Methotrexate and 5-fluorouracil were administered prior to the day 1 session. RESULTS: Methotrexate (1.0-32 mg/kg) alone failed to alter mean latency acquisition, retrieval, or reinforced response rates. Similar to scopolamine, a known amnesic in this assay, 5-fluorouracil (3-75 mg/kg) failed to alter response rates or acquisition latency on day 1 but significantly altered latency to retrieve a previously learned response on day 2. In combination, 3.2 mg/kg methotrexate plus 75 mg/kg 5-fluorouracil significantly increased day 1 and day 2 acquisition and retrieval latencies without altering response rates or motivation to respond as measured by progressive ratio responding. CONCLUSION: Taken together, these data demonstrate that 5-fluorouracil causes increased latencies for retrieval of previously learned behavioral responses and that combination of chemotherapeutic agents may produce greater delays than either agent alone, including when neither agent alone does so.