IS SUBLINGUAL SUFENTANIL DANGEROUS?

the anesthesia consultant

Physician anesthesiologist at Stanford at Associated Anesthesiologists Medical Group
Richard Novak, MD is a Stanford physician board-certified in anesthesiology and internal medicine.Dr. Novak is an Adjunct Clinical Professor in the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University, the Medical Director at Waverley Surgery Center in Palo Alto, California, and a member of the Associated Anesthesiologists Medical Group in Palo Alto, California.
email rjnov@yahoo.com
phone 650-465-5997

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Is sublingual sufentanil dangerous? The United States Food and Drug Administration (FDA) voted to approve the narcotic sufentanil for sublingual use in November of 2018. Sublingual sufentanil is 5-10 times more potent than fentanyl, and dissolves under the tongue in seconds.

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In an era of opioid overdose crisis, we now have a new, even more potent pill form of opiate.

Opioid deaths 1999-2017Sublingual sufentanil is approved for use only in medical settings, for the treatment of moderate to severe acute pain. But it is also possible that sublingual sufentanil will become the most dangerous street opiate ever known. This column reviews the arrival of sublingual sufentanil, from the viewpoint of a practicing anesthesiology attending.

Raeford Brown, Jr., MD, chair of the Anesthetic and Analgesic Drug Products Advisory Committee, and professor of anesthesiology and pediatrics at the University of Kentucky, disagreed with the FDA approval for sublingual sufentanil, citing the drug’s risk for “diversion, abuse, and death.” He cited the possible harms of such a “dangerous” drug — estimated to be 500-600 times more potent than morphine — coming to market in a tablet form. He warned of the risks of diversion of sufentanil by anesthesiologists and other medical personnel. He was quoted, “Sufentanil is a very potent opioid that is in a preparation that will be easily divertible. In the IV formulation, it has been a drug of abuse for health care providers.”

I agree with Dr. Brown. Sublingual sufentanil raises dangerous concerns. Sublingual sufentanil has the potential become the hydrogen bomb of all opiates—the mother of all lethal street drugs.

I have extensive experience administering intravenous sufentanil to patients. Intravenous sufentanil was FDA-approved in 1984. Its original primary use was as an anesthetic for cardiac surgery. I practiced cardiac anesthesia from 1985 until 2000. In the 1980s, cardiac anesthesia was achieved by high dose narcotic techniques, specifically with high dose fentanyl (100 micrograms/kg) techniques. For a 70-kilogram patient, this required injecting 7000 micrograms of fentanyl, or 140 ml of fentanyl (nearly two and an half sixty-milliliter syringes full of fentanyl) at the time of anesthetic induction. When intravenous sufentanil was approved at the same 50 mcg/ml concentration as fentanyl, but with a potency of 10 X of fentanyl, the narcotic induction only required 14 ml of sufentanil total. I can still remember my wide-eyed professors saying, “With sufentanil, the entire cardiac anesthetic is here in one syringe.” The use of sufentanil for cardiac anesthesia faded as anesthesiologists began using lower doses of narcotic as part of early-extubation techniques in the late 1990s.

We also used intravenous sufentanil to supplement anesthesia for non-cardiac surgeries. The most common method was to dilute the sufentanil 10:1 with saline, to a concentration of 5 mcg/ml. At this concentration, sufentanil was indistinguishable from fentanyl at 50 mcg/ml. After several years it became apparent that there was no advantage of using sufentanil IV over fentanyl IV in non-cardiac anesthesia, and the administration of IV sufentanil dwindled. The intravenous sufentanil form of the drug was also approved for epidural anesthesia. Over time, the use of sufentanil for epidural anesthesia also decreased, also supplanted by fentanyl.

Just when it looked like sufentanil was a drug nobody really neededà enter AcelRx Pharmaceuticals, a San Francisco Bay Area company which manufactured and tested a sublingual sufentanil product designed to melt under a patient’s tongue. Pamela Palmer, the founder and Chief Medical Officer of AcelRx, received her MD and PhD at Stanford, and is an acquaintance of mine. Dr. Palmer is an anesthesiologist who is brilliant and well informed regarding the pharmacology of sufentanil and the use of sufentanil in anesthetic practice.

Because sufentanil is highly lipid (fat) soluble, it is quickly absorbed into the bloodstream through the mucosal lining of the mouth. AcelRx will market the drug under the name Dsuvia, in a sublingual sufentanil tablet system (SSTS) which consists of a single-dose applicator prefilled with a single 3-mm-diameter 30-mcg tablet, administered by a healthcare professional no more frequently than hourly.

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A radio frequency identification (RFID) cartridge, requiring the patient’s thumbprint, helps reduce unauthorized dosing. The device is tethered to the patient’s bed to reduce risk of product loss. Each tablet is pre-loaded into a single-dose applicator within a pouch so it is suitable for field/trauma use. Both the fixed drug and dose and lockout time interval eliminate the end-user programming error risk associated with Patient Controlled Analgesia (PCA) intravenous narcotic pumps.

Studies documented the efficacy and safety of the SSTS in the treatment of postoperative pain in patients following open abdominal surgery compared with placebo.

SSTS was rated a success by significantly more patients when compared to intravenous PCA morphine. There was a faster onset of analgesia and both higher patient and nurse satisfaction scores with the SSTS as measured by validated questionnaires.

Dsuvia will be marketed as “postoperative, sublingual, patient controlled analgesia.” Once administered under the tongue, the sufentanil tablets typically dissolve within 5  minutes. The FDA approved the drug to be used in hospital settings only, for the treatment of moderate-to-severe acute pain, where a narcotic is needed and rapid onset is desired, but the route of administration does not require intravenous access. Typical settings would be the surgical wards after major orthopedic or general surgery procedures. The chief competition for Dsuvia will likely be Patient Controlled Analgesia (PCA) intravenous narcotic pumps, a commonly used analgesic method in which patients push a bedside button and self-administer intravenous narcotic (e.g. morphine, fentanyl, or Dilaudid) on demand through their IV line.

The most significant risk involving sublingual sufentanil is its potency, specifically its extreme potency as a respiratory depressant. The product description by AcelRx states that sufentanil has a “high therapeutic index” of 26,716. The Therapeutic Index is the ratio that compares the blood concentration at which a drug becomes toxic and the concentration at which the drug is effective. The larger the therapeutic index (TI), the safer the drug is. The TI affirms that sufentanil toxicity starts at a concentration of 26716 times its therapeutic concentration, but this ignores the risk of respiratory depression at much, much lower doses. A patient treated with an overdose of sufentanil will stop breathing at a dose only slightly greater, i.e. in the ballpark of only 2 – 4 times greater, than its therapeutic concentration. Like all opiates, sufentanil has side effects of respiratory depression, sedation, nausea and constipation. Respiratory depression is the reason why opiate overdose patients die. Opiate overdoses do not cause death because of an inherent “toxicity” of the drug concentration in the blood, but rather because of respiratory depression. People simply stop breathing.

Regarding sufentanil, the National Institute of Health website states: WARNINGS: Serious, life-threatening, or fatal respiratory depression has been reported with the use of opioids, even when used as recommended. Respiratory depression, if not immediately recognized and treated, may lead to respiratory arrest and death. Sufentanil Citrate injection should be administered only by persons specifically trained in the use of anesthetic drugs and the management of the respiratory effects of potent opioids, including respiration and cardiac resuscitation of patients in the age group being treated. Such training must include the establishment and maintenance of a patent airway and assisted ventilation. Adequate facilities should be available for postoperative monitoring and ventilation of patients administered anesthetic doses of Sufentanil Citrate Injection. It is essential that these facilities be fully equipped to handle all degrees of respiratory depression. Management of respiratory depression may include close observation, supportive measures, and use of opioid antagonists, depending on the patient’s clinical status.

There is also hope that sublingual sufentanil will have battlefield applications. A statement from FDA Commissioner Scott Gottlieg, MD on November 2, 2018 read: “(Sublingual sufentanil) has some unique features in that the drug is delivered in a stable form that makes it ideally suited for certain special circumstances where patients may not be able to swallow oral medication, and where access to intravenous pain relief is not possible. This includes potential uses on the battlefield. For this reason, the Department of Defense (DoD) worked closely with the sponsor on the development of this new medicine. This opioid formulation, along with Dsuvia’s unique delivery device, was a priority medical product for the Pentagon because it fills a specific and important, but limited, unmet medical need in treating our nation’s soldiers on the battlefield. The involvement and needs of the DoD in treating soldiers on the battlefield were discussed by the advisory committee . . . The FDA has made it a high priority to make sure our soldiers have access to treatments that meet the unique needs of the battlefield, including when intravenous administration is not possible for the treatment of acute pain related to battlefield wounds.”

In conclusion, will sublingual sufentanil be dangerous or not?

My assessment of sublingual sufentanil, based on the information above, is as follows:

  1. Sublingual sufentanil (SS) can be useful in hospitalized post-operative patients following major, painful surgeries such as orthopedic total joint replacements or intra-abdominal surgeries. SS could replace PCA intravenous morphine or fentanyl.
  2. The market share, or prevalence of SS use will largely depend on its cost versus intravenous PCA units. AcelRx will market the drug beginning in early 2019, at a wholesale price of $50 to $60 per dose. https://www.washingtonpost.com/national/health-science/fda-approves-a-powerful-new-opioid/2018/11/02/88cd27e6-deaf-11e8-85df-7a6b4d25cfbb_story.html?utm_term=.f4efacea46ad
  3. SS will not be frequently used in Post Anesthesia Care Units, Intensive Care Units, or the Emergency Department, because patients in these settings all have intravenous lines in place, and can receive traditional IV narcotics as needed. There is no need or demand for a sublingual narcotic product in these settings.
  4. If SS tablets are diverted or stolen and are taken outside of medical settings, they can cause death. Overdoses as low as two to four times a therapeutic dose could cause respiratory depression and death. If hospital personnel divert the drug for recreational use, these personnel will be at high risk for mortality.
  5. If SS ever reaches the streets as a recreational drug or heroin substitute, users will achieve opiate overdose and death at a very high rate. If anyone naively believes the drug will not reach the streets, consider that manufactured forms of all the other pill forms of opiates, i.e. Percocet, Vicodin, and Oxycodone, eventually reached the streets. What will prevent this new drug from doing the same?
  6. Efforts to educate street users regarding the dangers of this new drug will likely fail. There can be no safe use of SS outside a medical setting. People will likely overdose and die.
  7. Regarding battlefield use: In military settings where IVs are not common, the capacity to administer potent sublingual narcotic may become standard. But misuse and abuse in the military and on the battlefield are also possible. Tales of rampant drug abuse by soldiers in the Vietnam War are part of the lore of that conflict. Access to sublingual sufentanil in the military would need to be strictly confined and monitored.
  8. An added note: An intentional overdose with SS is probably an outstanding drug for physician-aided suicide.

I have no crystal ball, but the bottom line is this:

If sublingual sufentanil use is confined to acute care hospital settings, it will be useful and not dangerous. But if sublingual sufentanil reaches the streets as a drug of abuse, it will be lethal.

Time will tell which of these fates is the truth.

 

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