Antagonist as Hero?
- 1. Adam Marc Kaye
Naloxoneauto-injector was recently approved for the emergency treatment of suspected opioid overdose.Evzio will be the manufactures brand name. It will work in a manner similar to the epinephrine pen which is marketed for the acute treatment of anaphylaxis.
Caregivers will be expected to utilize this medication after an observation of possible symptoms of opioid overdose. Vague signs such as extreme sleepiness, breathing problems, or even “pinpoint” pupils may prompt a family member or close friend to whip out this life-saving device.
Paramedics and Physicians employed in emergency rooms have utilized this opioid antagonist for half a century for the treatment of suspected opioid overdose. Why is this medication being hailed as the best safety mechanism to prevent the epidemic of deaths of people in our country? What else can be done to reduce the unbelievable statistic of a death every 36 minutes from an opioid overdose in the United States? Will this new drug in the hands of laypeople really make a dent in this crisis that in recent years has actually surpassed car accidents as the leading cause of accidental death?
The FDA and physicians seeEvzio as a mechanism to combat opioid abuse. Rescheduling hydrocodone-based products to DEA schedule II along with creating more abuse-deterrent opioid formulations are other strategies being suggested by the medical community and government theorist. Risk Evaluation and Mitigation Strategies (REMS) which include FDA Mandated med-guides together with Rx monitoring programs have done very little possibly due to little cohesiveness between prescribers and pharmacists to address this problem and work toward the creation of a successful strategy to combat abuse and misuse.
For Evzio to be effective, it will have to be prescribed and probably paid for by either the patient or the prescription insurance company. Will the prescriber be willing to address the risk of opioid overdose to their patients on high-dose opioids or just those with known substance abuse or those with a history ofaddiction or past stays in detox programs?
I am all for prescribers suggesting Evzio to all their chronic pain patients on high-dose opioids. The need for anexplanation on the risk of respiratory depression and death is crucial even if the prescriber does not suspect abuse of opioids. Unintentional overdose is a common term used by physicians and medical examiners after patients consumed dozens of medications, often at extremely high doses-many not even prescribed. Sounds a lot like suicide? Most autopsy reports will not even suggest that a patient was attempting to take their life-without a suicide note!
This brings us back to the question of will this medication actually be used by a family member if they see someone on their couch breathing shallow?
It is unbelievable how much positivity is being reported with naloxone! Reports of it being without risk or side effects have suggested that the medication can be used by Good Samaritans who happen to be bystanders positioned around the country to assist doctors and reduce society concerns of opioid withdrawal. Caregivers must be educated about what to expect AFTER giving naloxone... sweating, goose-bumps, increased heart rate, agitation, withdrawal symptoms, and the lack of efficacy for overdoses of other medications that may be onboard including benzodiazepines,etc.
It is also very important to remain aware that most opioids will last longer than naloxone-so good luck encouraging patients to head on down to the emergency room additional dosed of naloxone, and further care including management of withdrawal symptoms.
With drug companies downplaying any cardiovascular complications or even side effects are associated with naloxone, it will be interesting to watch for sympathomimeticcatecholinergicsurge with a corresponding rapid pulse following naloxone administration. Myocardial Infarction/Stroke complications will occur especially in patients with risk factors including smoking history, obesity, sedentary lifestyle (from their chronic pain) or hypertension and tachycardia.
BP and HR go thru the roof after naloxone use and an increase in anxiety will make this inferred safe and easy treatment a very difficult situation for these non-medical professional bystanders.
This is not the first time that naloxone has been suggested as a panacea. Since naloxone is needed intravenously to reverse opioid overdose, researchers have tinkered with oral formulations for both treatment and reduction of associated complications.The ineffectiveness of laxatives to target the underlying cause of opioid-inducedinhibition of gastric motility and the resulting chronic associated constipation lead to the development of treatments that utilize opioid receptor antagonists including naloxone and methylnaltrexone to target receptorsin the gut preferentially.
It has been suggested that naloxone, when given orally, has negligible bioavailability but may actually counteract opioid induced constipation by blocking the action of opioid medications locally in the gut. Because of a sophisticated understanding of pharmacokinetic properties, naloxoneactivity in the gastrointestinal tractpresumably occursbefore metabolism by the liver and the necessary reduction to negligible drug activity in the CNS where opioid (pain) receptors are located. Central effects of the oral naloxone are minimized by utilizing sparse doses that benefit colon transit time and minimize complications that would impair analgesia.
Methylnaltrexonemarketed under the nameRelistor provides peripherally-acting-opioid antagonism that has the ability to reverse constipation in patients using opioid-agonists without affecting analgesia or even precipitating withdrawals. A permanently charged tetravalent nitrogen atom in its design prevents the crossing of the blood–brain barrier. This predominant antagonist effects counteracts troubling opioid induced side effects such as itching and constipation, all while not minimizingopioid effects in the brain responsible for analgesia.
The marketing ofoxycodone/naloxone tablets, and other fixed dose combination products including previously marketedpentazocine-naloxone andmorphine/ naltrexone utilized agonist/antagonist has been attempted in an effort to prevent reactions from crushing or injecting these combination products. Naloxone was considered a wonderful deterrent to oral pain medications in an effort to prevent a patient from crushing and injecting an oral opioid with the hope of getting a “greater high or euphoria rush”. The providing of warnings by physicians and pharmacists were thought to reduce the incidence of severe and potentially lethal misuse-reactions. Unfortunately, the morphine/naltrexone formulation was withdrawn not due to any failure by the science of the formulation including any insignificant amount of sequestered naltrexone reaching systemic circulation, but because of reports of potentially fatal reaction upon patient tampering and the subsequent release of naltrexone blunting the euphoria of opioids and precipitating dangerous opioid withdrawalsequelae in opioid-dependent patient.Suboxone (buprenorphine and naloxone) has become a very popular treatment for opiate addiction and while abuse is still possible, it appears to have less euphoria and powerful analgesia effects compared with full-agonists listed above.
Naltrexone basically has the same pharmacological effects as naloxone, but it is longer acting and does possess potent pharmacologic effects when used orally. Naltrexone is often utilized prophylactically to maintain abstinence from opioids and administered by specially trained medical supervision under anesthesia to provide rapid detoxification in addicted patients wishing to bypass the unpleasant withdrawal syndrome. Naltrexone for Opiate Dependence has not proven to be a breakthrough in allowing patients to remain free of opioids. Patients cannot be started on this preventative treatment until they have already been opioid free for at least a week due to its ability to precipitate an opioid withdrawal in opioid-tolerant patient.
Nature gave man opioid agonists and scientists have created antagonists to combat them. Which will prove the most powerful in the end? These antagonists sure are providing an interesting subplot to the battle between opioid agonists. Sometimes in medicine it is hard to determine what characteristics describe the antagonist heroes and that of the protagonist villain?
Kaye AM (2014) Antagonist as Hero? J Clin Pharm 1(1): 1001.