By: Kathlynn Ferrer, Pharm.D. Candidate c/o 2013

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Nabiximols (Sativex^®) is a buccal spray that has been approved for use in the UK, Spain, Germany, Denmark, New Zealand, and Canada. The active ingredients in this product are Tetrahydrocannabinol and Cannabidiol, two kinds of cannabinoids¹. Cannabinoids are chemical compounds that stimulate cannabinoid receptors and are the main chemicals in marijuana, a drug that has been Schedule I since 1937 and has been a subject of legal and medical controversies. Thanks to these active cannabinoids, one finds that the cannabinoid receptors CB1 and CB2 are stimulated leading to an analgesic state. Cannabinoid receptors are G-protein coupled receptors that are located in the brain (notably the midbrain), spinal cord, and peripheral nervous tissue (CB1) as well as the immune system (CB2), just to mention a few major areas. Stimulation of cannabinoid receptors inhibits the release of various neurotransmitters that can affect nociceptive neurons such as glutamate and GABA, as well as pro-inflammatory factors from other cells. Nociceptive neurons can cause pain that is somatic (typically more acute, occurs in the bone, joints, muscle, connective tissue, or skin) or visceral (more dull and persistent pain affecting internal organs) in nature, but cannabinoids have been noted to help with hyperalgesic states and neuropathic pain as well.²

In Canada specifically, Sativex^® is indicated for spasticity or neuropathic pain associated with multiple sclerosis (MS) as well as the management of moderate-to-severe cancer pain. Like a lot of other drugs listed for pain, or even just like all drugs in general, pertinent boxed warnings regarding a drug’s use are listed in the package insert. Boxed warnings listed in the Canadian package monograph for Sativex^® include the possibility of adverse cardiovascular effects, mental function changes (dizziness, changes in memory and perception), and drug dependence, as well as a warning to use cautiously in patients with a history of seizures. Some of the side effects of Sativex^® include nausea, vomiting, diarrhea, fatigue, dizziness, dry mouth, vertigo, confusion, and hypotension.³

A lot of positive research involving cannabinoids has been published and Sativex^® has been approved in a number of countries, but as unsurprising as it would sound Sativex^® is not currently approved for use in the United States. GW Pharma, the company that manufactures Sativex^®, has been making a push for approval in the US and has made progress over the last 6 years. An IND for the drug was accepted by the FDA in January 2006, allowing the company to start Phase III trials testing the drug in advanced cancer patients with pain not relieved by opioids. A Phase III trial evaluated Sativex^® for pain alleviation, reduction in opioid use for breakthrough pain, and other measures regarding improved quality of life.⁴ In April 2011, a patent was granted to GWPharma for the use of Sativex^® for cancer pain in the US while the drug was still undergoing Phase III trial testing.⁵ A few months ago in January 2012, an NDA for Sativex^® was finally submitted to the FDA with hopes for approval by the end of 2013.^6,7

In light of recent news, a couple of good points concerning Sativex^® has been brought up: if the drug can potentially be abused like regular marijuana or if the drug has a lot of side effects similar to marijuana, why then would this drug be possibly approved in the US? The abuse potential, dependency, and changes in mental function associated with marijuana are among some of the reasons why marijuana itself is deemed dangerous and remains a Schedule I drug in the US today.⁶ Perhaps the stigma of smoking marijuana from when it was first banned still resonates in society today. However, 16 states plus Washington DC have approved medical marijuana and some patients have benefitted from using the drug. Cannabinoids have been shown to help ease the severity of nausea and vomiting associated with chemotherapy (hence Nabilone [Cesamet^®] and Dronabinol [Marinol^®]) in addition to relieving pain.^6,8  Drugs like Sativex^® do have their relevance in medicine today.

Unless the FDA finds something remarkable from pre-existing evidence (e.g. from a Phase IV prevalence in Europe or Canada of a significant ADR) then Sativex^® may be approved for advanced cancer pain in the US in the future. This would be great in today’s market, as the only current practical option for addressing advanced cancer pain are the opioids. These drugs work to inhibit pain by binding to opioid receptors in the CNS, leading to a decreased perception of pain via inhibition of ascending pain pathways that start at the spinal cord. The main black box warning for these Schedule II drugs regards the possibility of abuse. Opioids are not without side effects as well, including respiratory depression, nausea, vomiting, sedation, fatigue, and constipation that don’t abate with prolonged use. Opioids are not created equal, as some are more potent than others. For example, fentanyl (Actiq^®, Fentora^™, Duragesic^®) is so potent that it would never be started on a patient who wasn’t previously opioid-tolerant.⁹

It is unsurprising that prescription drug misuse has been on the rise and opioids have been implicated heavily in relation. Unfortunately, prescription drug abuse has not decreased as of late and pain killers are implicated as the number one abused drug class. Opioid prescriptions have almost tripled over two decades.¹⁰ A string of pharmacy robberies and murders in Long Island recently reported in the news involved people who wanted to steal opioids. How many times have we encountered fake prescriptions for opioids while at work or rotations? These drugs have addictive properties and abuse can lead to a tolerance or dependence. Tolerance occurs when one’s ability to not sense pain is blunted; meaning more amounts of the drug is required to achieve one’s previous pain-blunting effect. Dependence is a more significant physiologic change where the discontinuation or reduction of an opioid dose or the addition of an opioid antagonist leads to withdrawal symptoms.  Addiction is more serious, psychological in nature, and is related to severe behavioral changes to get a drug as well as compulsive drug use.^9,10

Opioid use in this country has gotten out of hand and in many ways, their use merits the same stigma as a Schedule I drug. Opioids are technically narcotics, which by definition are psychoactive compounds that can induce somnolence. When abused, they can precipitate consequences similar to abused Schedule I drugs, including toxic effects such as low respiratory rate, low blood pressure, coma, and death – the only difference is that the opioids are legally available in the US.¹⁰ More notably, prolonged use of opioids can lead to a hyperalgesic state, which sounds counterintuitive. Opioid-induced hyperalgesia is an increased sensitivity to pain stimuli leading to an increased perception of pain. In this phenomenon, increasing the dose or frequency of opioids actually increases the amount of pain a patient experiences. This pain is more diffuse and is almost similar to how neuropathic pain develops.¹¹ Unlike opioid receptor agonists as mentioned earlier, cannabinoid receptor agonists have anti-hyperalgesic properties and have been helpful for neuropathic pain, adding to the value of using a drug like Sativex^®.

The above problems associated with opioids are not to disavow the medical benefit of the opioids but to point out that Sativex^® is an equivalent choice in decreasing pain and improving quality of life, both of which would be greatly beneficial to an advanced cancer patient. Having different options to help control pain, especially for a patient with advanced cancer, can help a patient believe in one’s analgesic therapy, make such patients feel more in control of their life altogether, and improve proper adherence. After all, a medication regimen is only as effective when a patient adheres to it. To reiterate, the drug’s effectiveness lead to its approval in other countries. Along with opioids, Sativex^® looks like a reasonable option for advanced cancer pain.

If the lack of safety is the reason for rejection of the NDA for Sativex^®, it would also be nice to see the government investigate the safety of opioids. Since opioids can be prescribed, they are possibly perceived as safe compared to illegal drugs – ultimately, any drug that is used improperly will put a patient in danger for various adverse effects.  For example, in theory if one continually overuses Sativex^®, dependence is possible. However, opioids pose that same exact risk. In many ways, Sativex^® and the opioids are similar to one another. A pharmacist’s intervention to counsel a patient on directions for the spray (for Sativex^®) or an explanation of the maximum daily dose (for both drugs) would promote effectiveness (pain alleviation) and minimize side effects (via stressing proper use) of either drug. Safety is definitely an important problem, but for a patient with advanced cancer pain, a patient who may very well only have a few months to live, decreased pain and improved quality of life may be equally important (if not even more important) than a drug’s safety. It will be interesting to observe whether the NDA for Sativex^® is accepted or rejected, the reasoning for its acceptance or rejection, and how the legality of marijuana and the safety of opioids are acknowledged in the process.

SOURCES:

1. Sativex. GW Pharma Website. http://www.gwpharm.com/Sativex.aspx. Last accessed March 21, 2012.
2. Manzanares J, Julian MD, and Carrascosa A. Role in the Cannabinoid System in Pain Control and Therapeutic Implications for the Management of Acute and Chronic Pain Episodes. Current Neuropharmacology. 2006; 4:239-257.
3. Sativex [Package Insert]. Salisbury, Wiltshire UK: GW Pharma Ltd; 2010.
4. FDA Accepts Investigational New Drug (IND) Application for Sativex. GW Pharma Website. http://www.gwpharm.com/fda-accepts-application.aspx. Last accessed Mar 21, 2012.
5. US Patent Granted for Sativex in Cancer Pain. GW Pharma Website. http://www.gwpharm.com/US%20Patent%20Granted%20for%20Sativex%20in%20Cancer%20Pain.aspx. Last accessed March 21, 2012.
6. Rettner R and MyHealthNewsDaily. Marijuana Mouth Spriay: Will Cancer Pain Reliever be Abused? Scientific American. http://www.scientificamerican.com/article.cfm?id=marijuana-mouth-spray. Last accessed March 21, 2012.
7. Marijuana-Based Drug Sativex May Get FDA Approval? NY Daily News. http://articles.nydailynews.com/2012-01-22/news/30653996_1_fda-approval-sativex-drug-companies. Last accessed March 21, 2012.
8. Should Marijuana be a Medical Option? ProCon.org. http://medicalmarijuana.procon.org/. Last accessed March 21, 2012.
9. Yaksh TL, Wallace MS. Chapter 18. Opioids, Analgesia, and Pain Management. In: Chabner BA, Brunton LL, Knollman BC, eds. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 12nd ed. New York: McGraw-Hill; 2011. http://www.accesspharmacy.com/content.aspx?aID=16663974. Last accessed March 21, 2012.
10. Topics in Brief: Prescription Drug Abuse. National Institute of Health. http://www.drugabuse.gov/publications/topics-in-brief/prescription-drug-abuse. Last accessed March 21, 2012.
11. Chang G, Chen L, Mao J. Opioid Tolerance and Hyperalgesia. Med Clin N Am. 2007; 91:199-211

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