Lately a new class of drugs have been pursued that might benefit virtually all of us due to the fact that it is being developed as a potentially safer alternative to the non-steroidal anti-inflammatory drugs (NSAIDs) which include aspirin, ibuprofen (NUROFEN), naproxen (NAPROSYN) and diclofenac (VOLTAREN) that we have grown so accustomed to popping when we suffer a headache, fever, cold*, flu*, etc. This class of drugs is so intriguing to me in particular because it takes an old herbal remedy that, despite its vital role in saving many and reducing the suffering of numerous others and has never claimed so much as a single life, has been criminalised without fair trial and deemed to serve no medical purpose, and turns it into a drug for which not only cannot kill but from what we can tell poses no potential for being used recreationally. The herbal remedy, of course, am referring to are the extracts of the cannabis sativa and cannabis indica (marijuana, hashish) plants and the new class of drugs are the fatty acid amide hydrolase (FAAH) inhibitors.
These drugs work by inhibiting the enzyme, fatty acid amide hydrolase (FAAH), which catalyses the degradation of a few biologically-active fatty substances the body synthesises known as fatty acid amides. The way how this relates to cannabis is that the fatty acid amides include the compound anandamide who’s roles in the body includes activating the cannabinoid CB1 receptor, which is the receptor the chief psychoactive constituent of cannabis, tetrahydrocannabinol (THC) activates in order to elicit its psychoactive effects. Interestingly, however, FAAH inhibitors, fail to produce many of the dose-limiting temporary side effects of cannabinoids (which are the compounds in, or related to those found in the cannabis sativa and indica plants) such as impairments in short-term memory, increased appetite which often can lead to obesity with chronic (long-term) use and motor deficits (trouble controlling voluntary movements with any degree of precision). To this end one phase I clinical trial (a clinical trial designed to establish the safety of a drug in healthy human volunteers and a safe, yet theoretically therapeutically optimal dosage range for the drug) which involved 32 adult volunteers randomised to receive the drug (and 8 randomised to receive placebo) demonstrated quite clearly that the first FAAH inhibitor to reach clinical testing, PF-04457845, was safe and well-tolerated (i.e. caused only mild and rare side effects).1
Unfortunately for a reason that completely baffles me in one randomised double-blind placebo-controlled phase II clinical trial involving patients with osteoarthritic pain in their knees PF-04457845 failed to produce a clinically-significant improvement in their pain compared to a placebo and naproxen-receiving groups that were also enrolled in this trial. I suspect, or hope rather, since this was such a promising potential target for new painkillers that were at least theoretically incapable of causing addiction and incapable of causing death on overdose or from rare side effects (I am basing this opinion on data that was obtained by testing the drug on laboratory animals, and what we know about it and related drugs based on how they interact with the molecular targets of the body), that either the dose was too low or it was being used against the wrong type of pain or there was some impurities in the drug they delivered to the patients that obscured the results.2
Another thing that gets me excited about FAAH inhibitors like PF-04457845 is that we have reason to believe that they would produce synergistic (additive) analgesic effects when used in combination with NSAIDs, paracetamol (acetaminophen in the US; PANADOL; TYLENOL in the US) and opioids like morphine, codeine, pethidine (meperidine in the US), oxycodone (OXYCONTIN), hydrocodone (VICODIN), methadone and fentanyl.
* NOTE: GIVING CHILDREN OR YOUNG ADULTS (ANYONE UNDER 25 YEARS OF AGE IS COUNTED UNDER THIS) WITH A COLD, FLU OR OTHER VIRAL INFECTION ASPIRIN IS SOMETHING YOU SHOULD NEVER EVER DO AS IT CAN LEAD TO A DIFFICULT-TO-TREAT AND FREQUENTLY FATAL CONDITION KNOWN AS REYE'S SYNDROME. REYE’S SYNDROME IN ADULTS HAS BEEN REPORTED AND HENCE IT IS ADVISABLE THAT ADULTS ALSO AVOID ASPIRIN WHILE THEY HAVE A COLD/FLU.
- Li GL, Winter H, Arends R, Jay GW, Le V, Young T, Huggins JP. Assessment of the pharmacology and tolerability of PF-04457845, an irreversible inhibitor of fatty acid amide hydrolase-1, in healthy subjects. Br J Clin Pharmacol. 2012 May [cited 2013 Jul 3];73(5):706–716. DOI: 10.1111/j.1365-2125.2011.04137.x
- Huggins JP, Smart TS, Langman S, Taylor L, Young T. An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee. PAIN [Internet]. 2012 Sep [cited 2013 Jul 3];153(9):1837–46. Available from: http://www.sciencedirect.com/science/article/pii/S0304395912002692
- Naidu PS, Booker L, Cravatt BF, Lichtman AH. Synergy between enzyme inhibitors of fatty acid amide hydrolase and cyclooxygenase in visceral nociception. J Pharmacol Exp Ther. 2009 Apr [cited 2013 July 3];329(1):48-56. DOI: 10.1124/jpet.108.143487