Fentanyl was first developed by Dr. Paul Janssen in 1959 under a patent held by his company, Janssen Pharmaceutical.
A potent analgesic and pain reliever — 100 times more potent than morphine and as much as 50 to 70 times stronger than heroin — the medical community quickly adopted it.
In the 1960s it was introduced as an intravenous anesthetic under the brand name Sublimaze, according to an article on News Medical Life Sciences by Ananya Mandal, MD
Following the popularity of Sublimaze, pharmacologists developed a variety of analogues: Sulfentani, Alfentanil, Lofentanil and Remifentanil.
Of the variants, Onsolis received FDA approval most recently. Onsolis is a soluble film of fentanyl on a disc that medical professionals place in the victim’s mouth. The victim’s body readily absorbs the drug, avoiding the possibility of inhalation. Medical professionals use most of the non-IV preparations primarily for breakthrough pain, particularly for cancer breakthrough pain.
Fentanyl has become available in a wide variety of applications since the mid-90s, including:
- Patches
- Lollipops
- Oral preparations
- Intramuscular injection
- Fentora buccal tablets
- Buccal spray
- Effervescent lozenges
- IV
- Internasal preparations
With so many modes of delivery, it is easy to see why the drug has such a potential for abuse. It has been estimated that more than 20,000 deaths of nearly 64,000 drug overdoses in the U.S. in 2016 were attributed to fentanyl overdose and analogues of it, or in combination with other drugs, according to the U.S. Centers for Disease Control and Prevention.
The power of fentanyl
Famous overdoses
Some high-profile cases include the death of Prince, also known as the Artist Formerly Known as Prince. According to Carver County (Minn.) attorney Mark Metz, the musician unknowingly took a counterfeit form of Vicodin laced with Fentanyl.
Musician Tom Petty suffered a similar fate as a result of fentanyl and other powerful analgesic agents he was taking while recovering from a hip fracture.
Fentanyl is a powerful opioid and acts on the central nervous system in a similar fashion to other opioids. This is because it is a full opioid agonist.
Fentanyl interacts primarily with the mu opioid receptors and binds to kappa and delta-type opioid receptors, according to the DrugBank database. These mu-binding sites are discretely distributed in the human brain, spinal cord and other tissues.
Clinical research
In clinical settings, the database reports that fentanyl exerts its principal pharmacologic effects on the central nervous system. Its primary actions of therapeutic value are analgesia and sedation. Fentanyl may increase the patient’s tolerance for pain. Alternatively, it may decrease the perception of suffering, although the presence of the pain itself still may be recognized.
In addition to analgesia, alterations in mood, euphoria, dysphoria, and drowsiness commonly occur. Fentanyl depresses the respiratory centers, depresses the cough reflex and constricts the pupils.
Fentanyl’s analgesic activity is most likely because of its conversion to morphine. Its intended effects include pain relief, sedation, analgesia and anesthesia. The main untoward side effect is respiratory depression to the point of complete respiratory failure as with other opiates.
However, as with any respiratory arrest, artificial ventilation and oxygenation is the treatment of choice. Treatment occurs with the administration of naloxone. Remember to titrate the naloxone in these instances. Providers must do this to maintain adequate respiratory drive and SPO2 without necessarily reversing naloxone’s therapeutic sedative or analgesic effects.
Or in the case of illicit overdose and/or addiction, titrated to maintain respiratory drive but not to cause withdrawal syndrome.
Other side effects include bradycardia, hypotension and non-epileptic myoclonic movement. When administered with neuroleptic agents there is a greater risk of hypotension.
Also in conjunction with drugs that affect serotonergic neurotransmission — such as selective serotonin re-uptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors — there is an increased risk of serotonin syndrome, which is potentially life threatening.
Side effects
Common side effects include:
- Labile blood pressure
- Tachycardia
- Hyperthermia
- Gastrointestinal symptoms
- Agitation
- Hallucination
- Hyper-reflexia
- Muscle rigidity
As previously mentioned, there are several routes of fentanyl administration. Most are some form of oral or mucosal route — buccal tablets and spray, nasal spray, effervescent lollipops and lozenges. These preparations aim to ease breakthrough pain. There is an oral tablet as well, but medical professionals should not administer it for short-term pain control.
The dosages of these short-term breakthrough pain control preparations range from 100 mcg to 800 mcg. Note that medical professionals must titrate them to effect. However, one can certainly see the potential for abuse and overdose. This proves especially true in children who see a “lollipop” or decide to stick patches on like Band-aids or stickers.
Adults could attempt to exceed recommended dosages in the midst of a bad breakthrough pain episode. As a result, the patient may lose consciousness and succumb to respiratory depression and failure.
The science behind fentanyl-induced chest wall rigidity
Along with the above issues, first responders should watch out for fentanyl-induced chest wall rigidity — often referred to as:
- Fentanyl chest
- Wooden chest
- Fentanyl chest syndrome
Although opioid muscule rigidity was first reported by Hamilton & Cullen in 1953, the actual mechanism is poorly understood. However, with fentanyl many think it occurs at a higher level in the nervous system than the spinal reflex.
The effect may be mediated through dopaminergic neurons in the basal ganglia as reported in the 2017 study “Fentanyl-induced chest wall rigidity syndrome in a routine bronchoscopy” published in Respiratory Medicine Case Reports.
Another proposed mechanism of increased muscle tone after the rapid infusion of an opioid (not specifically fentanyl) in an experimental animal study published in the Neurosci Lett in 1989 indicated stimulation of central mu1 opioid receptors increases efferent motor stimulation, resulting in muscle contraction and rigidity.
Additional data published in Anesthesiology in 1996 demonstrated that while systemic opiate-induced muscle rigidity is primarily caused by the activation of central mu receptors, supraspinal delta-1 and kappa-1 receptors might also attenuate this effect. Additional conjecture regards the principal source of central nervous system norepinephrine, for example, as the locus ceruleus.
It appears the involvement of the cerulospinal noradrenergic pathway is critical to the phenomenon of fentanyl-induced muscular rigidity, according to the Neurosci Lett study.
Additionally, the cerulospinal noradrenergic mechanism, the cerulospinal glutamatergic pathway and both NMDA and non-NMDA receptors in the spinal cord might mediate fentanyl-induced muscular rigidity. This was demonstrated in a rat population in a study published in Anesthesiology in 1997. That study reported fentanyl-induced muscular rigidity might involve disinhibition of spinal motoneurons via an action of norepinephrine and glutamate on separate neuronal areas within the spinal cord.
Spotting fentanyl-induced chest wall rigidity in the field
While the exact mechanism is unclear, what does seem to be common to most cases of fentanyl chest rigidity syndrome is the rate and dose of the drug given. When given at a rate of 150 mcg per minutes in healthy volunteers, at a dose of 15mcr per kg, rigidity occurred in about 3 minutes, according to the study “Fentanyl-induced rigidity and unconsciousness in human volunteers. Incidence, duration, and plasma concentrations” published in Anesthesiology in 1993.
Others have reported rigidity at much lower doses and slower administration time, 30-50 mcg per min and at doses of 7.3 to 8 mcg per kg, according to a study published in Anesthesia and Analgesia in 1970 and another study published in Anesthesiology in 1981.
Still others reported a case of a 22-year-old female in whom rigidity occurred with only 100 mcg over a 12-minute period.
Ackerman et.al. reported a similar episode after 100 mcg over 7 minutes. This phenomenon is more common with pediatric surgery patients, although the literature did not discuss an actual frequency, only that it is an uncommon occurrence but significant enough to be of concern to providers who undertake the use of fentanyl (or other opioids, particularly lipophilic synthetics).
One study of term and preterm neonates indicated eight out of 89 (8.9%) undergoing sedation with the use of fentanyl demonstrated muscular chest wall rigidity and two showed glottic rigidity and closure with laryngospasm, leading to hypoxia, hypercarbia and bradycardia. The dose was 3-5 mcg per kg , according to Fahnenstich et.al.
How to treat respiratory distress from fentanyl-induced chest wall rigidity
The apparent precipitating factor in this syndrome seems to be more the rate of administration and to a lesser extent the dosage. Although in several cases both dose (low) and rate (slow) appeared to precipitate the onset of the syndrome with respiratory arrest ensuing.
In some cases, the use of bag-valve mask ventilation was sufficient and adequate O2 saturation was maintained. However, in most cases bag-valve mask ventilation was impossible.
Thus, treatment requried the expedient use of naloxone , generally in fairly low doses, so as not to negate the analgesic affect. But rather it was titrated to ventilatory effect, often 0.2 to 0.4 mg increments.
In the case of inadvertent or intentional overdose, much higher doses of naloxone may be required. Additionally, one can use a short acting (or long acting) paralytic agent to correct the condition allowing for effective bag-valve mask ventilation.
A note to those who use fentanyl in rapid sequence induction procedure. If fentanyl chest wall rigidity occurs, simply procedure expeditiously to the paralytic. Then Narcan is recommended as de-saturation may occur rapidly due to increased oxygen demand caused by the spasming thoracic muscles — often including jaw, masseter, limbs, hyperthermia and possible acidosis if the episode is prolonged.
Though fentanyl-induced chest wall rigidity has proven uncommon — other than the study that reported 8.9% among term and preterm neonates — researchers have not performed actual randomized studies. The syndrome is potentially fatal if not recognized immediately and corrected.
The treatment for fentanyl-induced chest wall rigidity is readily available — naloxone, paralytic agents and re-induction — and all providers who undertake the use of fentanyl or other (particularly synthetic lipophilic) opioids should be aware of the syndrome and be adequately prepared to manage it should it occur.