08/5/15

Pleasant Dreams with Z-Drugs

© Todsaporn Udompon | 123rf.com

© Todsaporn Udompon | 123rf.com

“Frigatebird” glanced at the pillows next to him on the couch and started laughing hysterically because they were alive. “They had arms and legs and were married.” He didn’t really believe this; he knew it was a hallucination, but could see the pillows talking to one another. When he looked at his friend, Andy had four noses drifting around his face, gently waving “like a sea anemone waves in the current.” Someone named “Hyper Jesus” said she didn’t expect to psychically alter the physical makeup of her ceiling, have a lengthy discussion with a plastic bag, or have her bed turn into a planet inhabited by ants who thought she was a god. “Needless to say, I was surprised when all of that happened.” These were the reported experiences of individuals who took Ambien, the popular sleep aide medication.

In Medication Madness, Peter Breggin wrote that although Ambien has a different chemical structure than benzodiazepines, it affects the same neurotransmitter system. And it produces similar effects, including abnormal behaviors and addiction. Read “Downward Spiral” for a description of Ambien-related addiction and abnormal behavior in a 24 year-old Australian man. “Frigatebird’s” complete story (“Powerful Imagination Enhancer”) and that of “Hyper Jesus” (“Lilith and the Shadow People”) can also be read on Erowid, a pro drug website.

Dr. Breggin commented that the Ambien CR label described how patients in brief three-week trials developed hallucinations, disorientation, anxiety, depression, mental and physical slowing, depersonalization, disinhibition, euphoric mood, and mood swings. He added there was a special concerns section that also indicated the possibility of memory problems, tolerance, dependence and withdrawal. All of the above are related in the three stories noted above.

Given these concerns, it shouldn’t be surprising that zolpidem, the generic form of Ambien, was found by the CDC to be the most frequently identified psychiatric drug as the reason for emergency room visits. Not surprisingly, zolpidem was the 19th most frequently prescribed medication in 2013, with 41.5 million prescriptions.

Twenty-five percent of these visits required hospital admission, according to Quarter Watch. It seems that the problems were the result of a pattern of unsafe use—using higher doses than recommended and using it for a longer period of time than recommended. According to Quarter Watch, “Zolpidem is recommended for short term use, based on pivotal efficacy trials of 21-37 days. We found 68% of zolpidem patients were sustained users, with 3 or more prescriptions/refills and a mean of 229 days supply.”

A 2013 DAWN report by SAMHSA said that in 2010, there were 64,174 ER visits involving zolpidem. Thirty percent of them (19,487) were attributed to adverse reactions—adverse health consequences resulting from taking zolpidem. An ER visit was not included if an illicit drug was involved. The number of adverse reactions from zolpidem rose nearly 220% from those reported in 2005. Patients 65 and over represented the largest percentage of zolpidem-related ER visits involving adverse reactions (32%), followed by patients aged 45 to 54 (22%) and those aged 55 to 64 (20%).

Forty percent of these adverse reactions were from the person only taking zolpidem; 50% involved other pharmaceuticals: 21% from narcotic pain relievers; 14% from benzdiazepines; 19% from antidepressants; and 8% from antipsychotics.  “In one tenth (1,970 visits, or 10 percent) of visits, alcohol was the only substance combined with zolpidem.” See Table 1 in the 2013 DAWN Report for further data on additional drug combinations.

A 2014 DAWN report by SAMHSA reported that one third of the 20,793 ER visits in 2010 involving zolpidem were for overmedication—when a patient exceeds the prescribed or recommended dose. These overmedication visits may have involved other medications, but excludes visits involving drug-related suicide attempts and the use of prescription medications not prescribed to the person. The number of ER visits involving overmedication of zolpidem rose 107% from 21,824 in 2005-2006 to 42,274 in 2009-2010.

Thirty seven percent of ER visits were for overmedication of only zolpidem; 57% involved other pharmaceuticals: 25% from narcotic pain relievers; 26% from benzodiazepines; 19% from antidepressants; and 14% from antipsychotics. “About 13 percent involved alcohol combined with zolpidem.”

Researchers previously found that use of zolpidem in combination with other pharmaceuticals or alcohol was associated with increased likelihood of being admitted or transferred to the ICU.Findings in this report show that almost half of zolpidem-related ED visits involving overmedication resulted in hospital admission or transfer. More than two thirds of ED visits that resulted in hospital admission or transfer involved other pharmaceuticals, mostly other CNS depressant medications. CNS depression is the result of decreased brain activity, which may be caused by taking one or several CNS depressant medications and/or alcohol in combination that may then have cumulative depressant effects on the brain.These depressant effects include a decreased breathing rate, decreased heart rate, and loss of consciousness, possibly leading to coma or death.

While the previously reported adverse reactions were more common among older age groups, overmedication ER visits were more evenly distributed across all age groups. While 31% of patients aged 45 to 54 had the largest proportion of zolpidem-related ER visits involving overmedication, only 11% of those patients were 65 and older and 14% of those were between 55 and 64.

Besides Ambien, some other non-benzodiazepine sleep aides approved by the FDA are: Lunesta (eszopicione) and Sonata (zalepion). All three have a risk of dependency. All three carry warnings of possible sleep-related activities, such as: sleep-walking, sleep-driving, making and eating food, talking on the phone, having sex. “The next morning, you may not remember that you did anything during the night.” And they have similar serious side effects: sleep-related activities, abnormal thoughts and behaviors (more outgoing or aggressive behavior than normal, confusion, agitation, hallucinations worsening of depression, suicidal thoughts or actions), memory loss, and anxiety. The links for each of these three Z-drugs are to the FDA approved medications guides. And there are descriptions of individuals with psychoactive “experiences” with Lunesta and Sonata on Erowid as well.

Benzodiazepines and z-drugs are both Schedule IV controlled substances (they have the same addictive potential). Another similarity is that they are commonly used on a long-term basis instead of the recommended short-term basis. The long-term use of z-drugs and the resulting increased tolerance contribute to the problems discussed above with Ambien, adverse drug events and overmedication. Tolerance builds up with regular use, requiring more of the z-drug to get to sleep. I’ve known where a second medication was added; sometimes the off label use of antipsychotics. This brings in another whole set of potential side effects and adverse drug events.

A study published in the British Medical Journal on the effectiveness of so-called z-drugs (non-benzodiazepine hypnotics, like Ambien, Lunesta and Sonata) found that both the drug effect and the placebo response were “small and of questionable clinical importance.” But when the two were put together, there was a reasonably large clinical effect.

These data suggest that the placebo response is a major contributor to the effectiveness of Z drugs. The remaining effect needs to be balanced against the harms associated with these drugs. The substantial proportion of the drug response accounted for by the placebo response indicates the importance of non-specific factors in the treatment of insomnia. As the placebo effect is a psychological phenomenon, these data suggest that increased attention should be directed at psychological interventions for insomnia.

If individuals aren’t informed of the dangers of mixing z-drugs and other medications like opioids, antidepressants and benzodiazepines, they are an adverse drug event waiting to happen. Because of the physical tolerance that can develop, rebound insomnia is likely if the medications are tapered too quickly. It may even occur with a gradual taper in some people. And then to top it all off, the z-drug effect was small and of questionable clinical importance. But on the other hand—maybe your pillow will dance; or you’ll become a god to nonexistent ants crawling around on your bed. Pleasant Dreams!

08/3/15

Is the Cart Before the Horse?

11088571_sSenators Dianne Feinstein and Charles Grassley wrote a brief article for Time that highlighted the effectiveness of CBD oil, a product derived from cannabis, in treating the debilitating seizures of a little girl. Her father, an ER doctor, said it took just 36 hours to see profound changes. However, CBD (cannabidiol) oil is not approved by the FDA; and there is no guarantee that the formulation of each batch will be the same. A one-month supply can cost up to $2,500; and the girl’s parents are forced to pay $100 per bottle if they want to verify the contents. “Simply put, we need to know more about CBD, and the only way to gain that knowledge is to remove barriers to research.”

The Time article has a 16-minute video linked, which reviews the issue in more detail and mentions some of the problems with the current state of regulation and research into medical marijuana. I’ve written several other articles on the legalization of marijuana and have a concern that the current practice of state-by-state approval is creating greater problems for the legitimate use of medicinal cannabis products; problems that must be addressed by federal action. The potential for CBD products should be fast tracked to confirm their medicinal use.

Currently, medical marijuana products are typically high in THC, the psychoactive cannabinoid in marijuana, and low in CBD. Compared to CBD, THC has limited medical benefits. But it is the only “therapeutic” agent in the vast majority of medical marijuana products. It seems this crucial and basic understanding of medical marijuana is not widely known or understood. It may be that many “medical” marijuana users don’t care. But it begs the following question—is the current process of state-by-state approval just a “smoke screen?” Is what is actually happening with medical marijuana just the first stage of national legalization of recreational marijuana use?

There is real, legitimate potential for the use of cannabis-based medicines. But they should pass through the same FDA gauntlet that other medicines have, even though the process itself in not perfect. It was put in place because of past abuses and the resulting dangers to public consumers from other so-called miracle cures. Let’s not ignore the past and repeat its mistakes.

The June 23/30 2015 issue of JAMA, The Journal of the American Medical Association, contained several articles related to medical marijuana. Three of them are reviewed below. They address both the potential benefits and consequences with medical marijuana. One article raises the concern embodied in the title of this article: are we putting the cart before the horse in rushing to approve medical marijuana without taking the time to scientifically assess its pros and cons?

Vandrey et al. in a JAMA research letter reported on edible cannabis products that they purchased from three randomly selected dispensaries in three cities: Los Angeles, San Francisco, and Seattle. Of the 75 different products purchased from 47 different brands, only 17% were accurately labeled with respect to their THC content. Twenty-three percent were underlabeled (contained more THC than claimed on the label); and 60% were overlabeled (contained less THC than claimed on the label). Some of the overlabled products contained negligible amounts of THC.

The non-THC content of tested products was generally low. Forty-four products (59%) contained detectable levels of CBD. But only 13 had their CBD content labeled. Four products were overlabeled and nine were underlabeled.

Whiting et al. did a systematic review and meta-analysis, “Cannabinoids for Medical Use,” of randomized clinical trials of cannabinoids for various conditions: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity from multiple sclerosis or paraplegia, depression anxiety disorder, sleep disorder, psychosis, glaucoma or Tourette syndrome. They used a methodology designed to reduce the risk of publication bias in their analyses.

The study concluded there was moderate-quality evidence for the use of cannabinoids (smoked THC and nabiximols) to treat chronic pain and spasticity. There was low-quality evidence to support using cannabinoids for nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders and Tourette syndrome. There was very low quality evidence for improvement in anxiety as assessed by a public speaking test. There was some evidence that cannabinoids (mainly nabiximols) were associated with an improvement in sleep. There was no evidence showing that cannabinoids helped in the treatment of depression or glaucoma.

Cannabinoids were also found to be associated with increased risk of short-term adverse events such as: dizziness, dry mouth, nausea, fatigue, drowsiness, euphoria, vomiting, disorientation, confusion, loss of balance and hallucination. The two studies that assessed the association between psychosis and cannabis found no difference in mental health outcomes, but they were judged to be at high risk of bias. There were no identified studies of long-term adverse events of cannabinoids, even when the searches were extended to lower levels of evidence than established in the initial methodology.

Doctors D”Souza and Ranganathan wrote an editorial for the same issue of JAMA, “Medical Marijuana: Is the Cart Before the Horse?” They raised the same concern Whitling et al. found, namely that for most of the indications that qualify by state law for medical marijuana, the supporting evidence for its use is of poor quality. “For most qualifying conditions, approval has relied on low-quality scientific evidence, anecdotal reports, individual testimonials, legislative initiatives, and public opinion.” So state and federal governments should support and encourage research so that high quality research on medical marijuana can be done for the conditions for which the existing evidence is insufficient or of poor quality.

They also noted how there are inconsistencies from state to state in how conditions are qualified for medical marijuana use. One example noted was that posttraumatic stress disorder was approved as a qualifying condition in some, but not all states. Unlike most FDA-approved drugs, marijuana has over 400 compounds; and there isn’t a uniform composition of the cannabis preparations. “Given the variable composition, patients will have to experiment with different strains and doses to achieve the desired effects,” a process known as titrating. The patient is looking for the personal Goldilocks dose—not too high and not too low.

While the acute adverse effects are known, the effects of repeated exposure, as would occur with medical marijuana needs further study. The risk of addiction, and a smaller risk of psychotic disorder were discussed. The interaction of marijuana with other drugs concurrently prescribed needs further study. They suggested that medical marijuana be added to monitoring databases along with opioids and benzodiazepines, so doctors would have a more complete understanding of the medication profile of their patients.

The human endocannabinoid system is involved in a variety of physiological processes such as appetite, pain-sensation, mood and memory. And there are two known cannabinoid receptors, CB1 and CB2. THC is a direct “fit” with the CB1 receptor, while another cannabinoid, cannabinol fits with CB2. The receptors are predominantly found in the brain (CB1) and the immune system (CB2). Cannabidiol (CBD) does not directly fit with either receptor, but has powerful indirect effects that are still being studied. See this graphic representation of the human endocannabinoid system.

“Emerging evidence suggests that the endocannabinoid system is critical in brain development and maturation processes, especially during adolescence and early adulthood.” This ongoing development of the system during adolescence then raises questions on what age exposure to medical marijuana is justifiable. Brain development continues until the age of 25. “Changes in the endocannabinoid system have been linked to affective, behavioral, cognitive and neurochemical consequences that last into adulthood.”

In conclusion, if the states’ initiative to legalize medical marijuana is merely a veiled step toward allowing access to recreational marijuana, then the medical community should be left out of the process, and instead marijuana should be decriminalized. Conversely, if the goal is to make marijuana available for medical purposes, then it is unclear why the approval process should be different from that used for other medications. Evidence justifying marijuana use for various medical conditions will require the conduct of adequately powered, doubleblind, randomized, placebo/active controlled clinical trials to test its short- and long-term efficacy and safety. The federal government and states should support medical marijuana research. Since medical marijuana is not a life-saving intervention, it may be prudent to wait before widely adopting its use until high-quality evidence is available to guide the development of a rational approval process. Perhaps it is time to place the horse back in front of the cart.