Nashua Pain Management Corporation 154 Broad Street Nashua, New Hampshire

Webster published: “The primary cause of death related to opioid overdose is hypoxia caused by opioid-induced respiratory depression… Interaction of opioids with l-opioid receptors located throughout the central nervous system, including those in the respiratory centers of the brainstem, can cause a reduction in respiratory drive… In addition, opioid treatment can suppress peripheral chemoreceptors, thereby blunting the response to hypoxemia and hypercapnia. … The combined suppressive effects of these processes may lead to respiratory depression (the medical outcome that occurs when inadequate ventilation of the lungs decreases the rate of gas exchange) and potential death… the reduction in respiratory drive with oxycodone 30 mg was statistically significant at 1 h post dose (P = 0.007)…. this was a small, well-controlled study with only 19 subjects in the safety population…. larger clinical studies are needed to provide a broader safety profile… It should be noted that these subjects were relatively young, healthy, non-obese, and without serious comorbid conditions. Thus, they may have been less susceptible to any potential effects on respiratory drive than elderly patients or patients with serious comorbid conditions who may be taking these drugs to relieve chronic pain. Also, the subjects selected for this study were not taking multiple drugs (other than for TEAEs) and were also fully alert/not sedated.  It is likely that many patients taking opioids for chronic pain may have underlying comorbid conditions that require multiple medications, which potentially increases the likelihood of opioid-induced respiratory depression [such as benzodiazepines as well as barbiturates which act at benzodiazepine receptors to suppress breathing during sleep], especially during sleep.” 

(Webster LR, Hansen E, Cater J, Smith T. A Phase I Placebo-Controlled Trial Comparing the Effects of Buprenorphine Buccal Film and Oral Oxycodone Hydrochloride Administration on Respiratory Drive. Adv Ther. 2020;37(11):4685-96.) 

Webster studied healthy awake individuals in whom ventilation (breathing) reflex is bolstered by conscious drive to breathe. When sleeping, only the reflex maintains breathing. When breathing (ventilation) reflex drive is stopped due to opioids and/or benzodiazepines and/or barbiturates and/or alcohol, oxygen required for cellular respiration to create energy to live stops. Without energy, death occurs. When respiration cellular metabolism ceases, ventilation airflow into the body ceases. 

Yet once again it is recognized that the primary mechanism by which prescription and illegal opioids suppress breathing to cause death is by consumption within hours of proximity to sleep. 

Thus, Webster’s article is misleading in that peer reviewed publication by Geller in Cleveland Clinic Journal of Medicine stated: “The DEA reported “most narcotic deaths are a result of respiratory depression.” (http://www.dea.gov/pubs/abuse/4-narc.htm, www.dea.gov accessed 11/8/15)  The American Pain Society stated “no patient has succumbed to [opioid] respiratory depression while awake.”(American Pain Society, Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, 1999, 4th ed., pg. 30.)(Geller AS. Opioid therapy and sleep apnea. Cleve Clin J Med. 2017 Feb;84(2):91-4.) 

Fundamentally, Webster should have studied the effects of the opioids when consumed in proximity to sleep as this is the time during which opioids cause death.  To study during waking hours, the results are substantially misleading and with far less clinical value to save lives.  Webster himself has acknowledged this in a number of his prior valuable publications over the years which focus on opioids suppressing ventilation during sleep to cause respiratory failure which then terminates ventilation and life. 

Webster simply again supported the ventilatory safety of opioids during waking hours when patients are working and their employer prevents them from napping / sleeping, affirming the breathing safety (if patients are educated and prescribed to not consume in proximity to sleep) of opioids independent of addiction and other risks. 

As peer reviewed published by Geller in JAMA: “Within one hour of ingestion of just 15 mg of oxycodone at 2AM, precipitation of 91 central sleep apnea events occurred in a patient with chronic pain receiving long-term opiate therapy who previously showed no sleep apnea.(Mogri M, Khan MI, Grant BJ, Mador MJ. Central sleep apnea induced by acute ingestion of opioids. Chest. 2008 Jun;133(6):1484-8.)  Similarly, within 30 minutes following 1AM ingestion of just 7.5 mg of hydrocodone, oxygen desaturation to 70% occurred with events more prevalent during NREM sleep.(Farney RJ, Walker JM, Cloward TV, Rhondeau S. Sleep-disordered breathing associated with long-term opioid therapy. Chest. 2003 Feb;123(2):632-9.)” (Geller AS. Opioid overdose-related deaths.  JAMA. 2011 July 27;306(4):379.)