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Gabapentinoids have been approved for treatment of neuropathic pain for conditions such as spinal cord injury or post-herpetic neuralgia¹. This class of drugs includes gabapentin and pregabalin. With growing concern over the current opioid epidemic, use of gabapentinoids has increased drastically to decrease prescription of opioids and to reduce acute and chronic pain after surgery². The American Pain Society supports the use of gabapentinoids in the perioperative period, but more recently, researchers have shown skepticism toward the efficacy of gabapentinoids.

Gabapentinoids, structural analogs of γ-aminobutyric acid, bind to presynaptic voltage-gated calcium channels and regulate the release of excitatory neurotransmitters. Specifically, these compounds inhibit glutamate release from pain-transmitting neurons, decreasing pain signals³. Gabapentin absorption takes place in a limited area in the duodenum, and pregabalin absorption takes place in the small intestine. Both drugs exhibit similar adverse effects, including dizziness, headache, visual disturbances, and peripheral edema, but trial results indicate that gabapentinoids are generally well-tolerated⁴.

A study conducted by Khan et al. studied patients who received gabapentin before and after lumbar laminectomy. Patients reported lower pain scores at every time point within the first 24 hours when receiving 900 or 1200 mg of gabapentin compared to placebo or 600 mg of gabapentin⁵. Another study also exhibited positive correlation between higher dosage of gabapentinoids and higher efficacy. The results showed that higher doses of gabapentin (900-1500 mg) more effectively reduced pain and opioid use after surgery⁶. Buvanendran et al. administered either placebo or 300 mg pregabalin to patients before their knee replacement surgeries. Patients in the pregabalin group reported little or no postsurgical chronic pain after three months, while 8.7% of patients in the control group reported pain⁷. Research conducted on pregabalin and gabapentin indicate similar pain reduction potential; however, there is more research on gabapentin, and gabapentin is more cost-effective.

However, more recent research indicates that researchers are no longer confident in the efficacy of gabapentinoids. Verret et al. published a study this year that included 281 trials in a meta-analysis. The study focused on the intensity of postoperative acute pain, cumulative opioid use, and adverse events. Contrary to previous studies, Verret pointed out that there should be a minimally important difference threshold for pain intensity, which was set at ten points in a pain intensity scale out of 100. Out of 24,682 participants, the average difference in pain intensity between the gabapentinoids and control groups was below ten points, which was below the statistically significant difference threshold. This pattern was evident at 6, 12, 24, and 72 hours after surgery. The gabapentinoids group did not exhibit more adverse events than the control group. On average, gabapentinoids reduced postoperative nausea and vomiting, but increased incidence of dizziness. This most recent study concluded that gabapentinoids did not exhibit any clinically significant benefits as perioperative analgesics.²

Past study results have encouraged the use of gabapentinoids both preoperatively and postoperatively. Off-label use of pregabalin and gabapentin has increased in the past decade due to fear of opioid abuse. Recent stances on gabapentinoids have become unclear, as more researchers begin to question its efficacy. Future research should attempt to answer discrepancies between past and present research.

References

1. 1. Peter C. Schmidt, Gabriela Ruchelli, Sean C. Mackey, Ian R. Carroll; Perioperative Gabapentinoids: Choice of Agent, Dose, Timing, and Effects on Chronic Postsurgical Pain. Anesthesiology 2013;119(5):1215-1221. doi: https://doi.org/10.1097/ALN.0b013e3182a9a896.

1. 2. Michael Verret, François Lauzier, Ryan Zarychanski, Caroline Perron, Xavier Savard, Anne-Marie Pinard, Guillaume Leblanc, Marie-Joëlle Cossi, Xavier Neveu, Alexis F. Turgeon, the Canadian Perioperative Anesthesia Clinical Trials (PACT) Group; Perioperative Use of Gabapentinoids for the Management of Postoperative Acute Pain: A Systematic Review and Meta-analysis. Anesthesiology 2020;133(2):265-279. doi: https://doi.org/10.1097/ALN.0000000000003428.

1. 3. Weinbroum, AA Non-opioid IV adjuvants in the perioperative period: Pharmacological and clinical aspects of ketamine and gabapentinoids. Pharmacol Res. (2012). 65 411–29
3. 4. Zhang, J, Ho, KY, Wang, Y Efficacy of pregabalin in acute postoperative pain: A meta-analysis. Br J Anaesth. (2011). 106 454–62
5. 5. Khan, ZH, Rahimi, M, Makarem, J, Khan, RH Optimal dose of pre-incision/post-incision gabapentin for pain relief following lumbar laminectomy: A randomized study. Acta Anaesthesiol Scand. (2011). 55 306–12
7. 6. Van Elstraete, AC, Tirault, M, Lebrun, T, Sandefo, I, Bernard, JC, Polin, B, Vally, P, Mazoit, JX The median effective dose of preemptive gabapentin on postoperative morphine consumption after posterior lumbar spinal fusion. Anesth Analg. (2008). 106 305–8
9. 7. Buvanendran, A, Kroin, JS, Della Valle, CJ, Kari, M, Moric, M, Tuman, KJ Perioperative oral pregabalin reduces chronic pain after total knee arthroplasty: A prospective, randomized, controlled trial. Anesth Analg. (2010). 110 199–207

Assessment of long-term outcomes is essential in brain surgery. While most studies have traditionally focused on the short-term consequences of brain surgery, more researchers are now reporting long-term outcomes in various cohorts of patients following a variety of invasive neurological interventions [1]. Given the complexity of brain surgery and numerous dangers it poses, healthcare professionals should be knowledgeable about the potential lasting effects of brain surgery so they can provide the best support to recovering patients.  

Before surgery, patients are typically aware of the well-known risks like bleeding and infection, but new research suggests that brain surgery can lead to more lasting issues with critical thinking and memory [2]. In a 2019 study conducted at the University of Wisconsin, researchers found that major neurological surgery is associated with a small and immediate cognitive decline, equivalent to less than five months of aging. The data from the study also suggests that, on average, patients who have brain surgery are nearly twice as likely to experience a decline in cognitive function in the years following their surgeries [3]. However, it is important to note that Dr. Robert Sanders, the senior author of the study, emphasizes that this doubling in risk only affects a small number of patients [3].  

Post-operative cognitive decline is thought to be caused by the immune system’s inflammatory response to surgery [2]. Brain surgery is considered a traumatic event for the body, resulting in the engagement of the immune system and an inflammatory cascade that affects the synaptic plasticity in brain regions involved in learning and memory [2]. If trauma-induced inflammation is not carefully regulated, patients could experience more than a minor cognitive decline [2].  

Even the youngest of patients seem to be susceptible to cognitive decline associated with brain surgery. Over the past 15 years, numerous studies have pointed to an association between commonly used anesthetics and sedatives in surgery and neurodegenerative changes in developing brains [4]. One 2017 study compared the IQ test scores and school grades of two groups of children: those who underwent surgery before the age of four (33,514 children) and those who had no history of surgery (159,619 children) [5]. The results indicate that exposure to surgery with anesthesia before the age of four is linked to lower IQ test scores and poorer academic performance [5].  

Healthcare providers should also be aware that patients who have had brain surgery are at an increased risk for developing depression. In 2008, a study examined the anxiety and depression levels of 72 patients before and after surgery to remove a primary brain tumor [6]. Before brain surgery, 50% of study participants showed general anxiety and 9.7% showed current depression [6]. Anxiety was assessed using the State and Train Anxiety Inventory, and depression was measured using the Zung Self-Rating Depression Scale [6]. Study participants were reassessed at both one month and three months after brain surgery [6]. The data showed no significant change in the percentage of patients with anxiety [6]. However, there was a significant increase in the percentage of patients with depression [6]. These results suggest that a depressive state can develop after brain surgery.  

It is important for healthcare professionals to understand the long-term effects of brain surgery so that recovering patients can be appropriately monitored and supported. Although the lasting effects are dependent both on the extent and location of the operation and the patient profile, healthcare professionals should be attentive to any cognitive or mood changes in patients who have experienced brain surgery.  

References

1. Tellez-Zenteno, J. F., R. Dhar, L. Hernandez-Ronquillo, and S. Wiebe. 2007. “Long-Term Outcomes in Epilepsy Surgery: Antiepileptic Drugs, Mortality, Cognitive and Psychosocial Aspects”. Brain 130 (2): 334-345. doi:10.1093/brain/awl316.  

2. Saxena, Sarah, and Mervyn Maze. 2018. “Impact on The Brain of The Inflammatory Response to Surgery”. La Presse Médicale 47 (4): e73-e81. doi:10.1016/j.lpm.2018.03.011.  

3. Krause, Bryan M, Séverine Sabia, Helen J Manning, Archana Singh-Manoux, and Robert D Sanders. 2019. “Association Between Major Surgical Admissions and The Cognitive Trajectory: 19 Year Follow-Up of Whitehall II Cohort Study”. BMJ, l4466. doi:10.1136/bmj.l4466.  

4. Andropoulos, Dean B. 2017. “Effect of Anesthesia on The Developing Brain: Infant and Fetus”. Fetal Diagnosis and Therapy 43 (1): 1-11. doi:10.1159/000475928.  

5. Glatz, Pia, Rolf H. Sandin, Nancy L. Pedersen, Anna-Karin Bonamy, Lars I. Eriksson, and Fredrik Granath. 2017. “Association of Anesthesia and Surgery During Childhood with Long-Term Academic Performance”. JAMA Pediatrics 171 (1): e163470. doi:10.1001/jamapediatrics.2016.3470.  

6. D’Angelo, Cristina, Antonio Mirijello, Lorenzo Leggio, Anna Ferrulli, Vincenzo Carotenuto, Nadia Icolaro, Antonio Miceli, Vincenzo D’Angelo, Giovanni Gasbarrini, and Giovanni Addolorato. 2008. “State and Trait Anxiety and Depression in Patients with Primary Brain Tumors Before and After Surgery: 1-Year Longitudinal Study”. Journal of Neurosurgery 108 (2): 281-286. doi:10.3171/jns/2008/108/2/0281. 

A quick glance around a typical household kitchen reveals a surprising truth: contained therein are the founding mechanisms used to administer anesthesia. The humble beginnings of sponges, towels, and handkerchiefs have evolved into the computerized self-sufficient anesthesia machines used today.

William Morton, a dental surgeon, publicly demonstrated the first successful pain-free surgery using ether anesthesia in 1846. For delivery, he used a glass globe with two valves for the inhalation and diffusion of ether vapor as air circled through. The contraption contained a sponge soaked in ether liquid for expanding the evaporation surface [1]. However, there loomed dangers of uncontrolled ether concentrations and varying amounts of anesthesia required for sedation [2]. Chloroform, a liquid anesthetic, decreased the heart rate more than ether, making it crucial to find a method for controlled administration [3]. By 1847, physician John Snow devised a machine to control vapor pressure using water to stabilize temperature and metal spiraled air passages to saturate ether. With many doctors unwilling to give up simplistic methods and learn complex apparatuses, Snow’s invention of a controlled ether inhaler was largely ignored [4].

Nitrous oxide gas catalyzed a turning point for anesthetics. Its harmless ability to stimulate rather than depress the nervous system and to quickly sedate without irritating the lungs, trumped the risks of ether and chloroform [5]. In 1865, a dental company began manufacturing impractical appliances requiring the immense efforts of holding a wooden mouthpiece while plugging patients’ noses to inhale gas from a bag. Liquid-form nitrous oxide avoided these nuances and began being sold in cylinders attached to a maze of bags, valves, and a mask [6]. To counteract the lack of oxygen in this arrangement, physiologist Paul Bert designed a hyperbaric pressure chamber providing 15% oxygen and 85% nitrous oxide but was unaware of oxygen toxicity at high pressures [7]. Eventually, the dental company’s initial flawed gas bag was redeemed with one of the first representations of an anesthesia machine. With pressure-regulating valves directing gas into a mixing chamber for oxygen and nitrous oxide, patients were safely sedated [4]. A milestone in medicine, anesthesia began transforming into a working machine.

The next century, anesthesia machines faced the challenge of accurately measuring gas concentration and flow. Initially, flow meters were used that relied heavily on the human eye to measure flow pressure based off of bubbling rates of water and moving bobbins. Gradually, rotameters replaced these, allowing medical professionals to self-calculate flow rate from the force of gas exertion. To preserve gas emissions from flow meters, pressure-controlled ventilators were introduced, depending on patients’ lungs to drive pressure and volume flow, but human error still remained [8].

In 1950, Snow’s achievement of temperature stabilization was implemented in new vaporizer designs. Now, delivery of liquid anesthesia depended only on flow rate and temperature. Though “variable bypass vaporizers” eliminated human calculation, they still required manual control to adjust concentrations [4]. With promising results from a computer-controlled anesthesia machine demonstration in 1978, manually operated vaporizers became computer- powered. Monitor feedback directed vaporizers to pump the amount of liquid anesthetic needed for specific vapor concentrations, offloading manual work — and marking the beginning of the twenty-first century.

With corporations releasing different prototypes, hospital workers spoke of “spaghetti syndrome,” as they jumbled up an array of cords from various machines [9]. Responding to these outcries, companies introduced monitors, anesthesia machines, and ventilators in one complete set to create the anesthesia workstation. From sponges to computers, the evolution of the anesthesia machine has now culminated in a single, portable, computerized station. Ideally, future evolutions will continue to safeguard the balance between computer and human responsibilities.

References

[1] Duncum B. (1994). The Development of Inhalation Anaesthesia. Royal Society of Medicine Press Ltd, London, 553-9, 106-8

[2] Bigelow, H. J. (1846). Insensibility during Surgical Operations Produced by Inhalation. The Boston Medical and Surgical Journal, 35(16), 309–317. https://doi.org/10.1056/nejm184611180351601

[3] J. Y. Simpson. (1958). New Anaesthetic Agent as a Substitute for Sulphuric Ether in Surgery and Midwifery, BJA: British Journal of Anaesthesia, Volume 30, Issue 11. 545 550, https://doi.org/10.1093/bja/30.11.545

[4] Eger, E. I., Saidman, L. J., & Westhorpe, R. N. (2014). Anesthesia Machines and Breathing Systems: An Evolutionary Success Story. The Wondrous Story of Anesthesia, 9781461484417, 703–714. https://doi.org/10.1007/978-1-4614-8441-7

[5] Weyde, V. (1864). Nitrous Oxide Gas. The New York Times. Retrieved from https://www.nytimes.com/1864/05/28/archives/nitrous-oxide-gas.html

[6] Thomas, K. B. (1976). The Development of Anaesthetic Apparatus. The 2 Oxide Series, 45(1), 74-103. https://doi.org/10.1097/00000542-197607000-00030

[7] Neuman, T. (2008). Physiology and medicine of hyperbaric oxygen therapy. Philadelphia, PA: Saunders Elsevier. 7-9

[8] Dorsch, J. A., & Dorsch, S. E. (2012). Understanding anesthesia equipment: Fifth edition. Understanding Anesthesia Equipment: Fifth Edition. 1–1056. Wolters Kluwer Health Adis (ESP).

[9] Westhorpe, R. N. (1992). The anesthetic machine in the 1990s. Anesthesiology Review. 46-55.

Safe anesthetic management of patients at risk for or who carry a diagnosis of obstructive sleep apnea (OSA) is imperative to guiding this subset of patients through the perioperative period. OSA carries perioperative risk both due to the direct respiratory effects of the disease, comorbidities of patients with OSA, as well as the associated long-term sequelae of patients with untreated or severe OSA. There is a relatively low number of studies examining best practices in anesthesia regarding patients with OSA, so much of the literature and recommendations focus on small studies and expert opinion. 

OSA is a disorder where upper airway tissue collapses into the upper airway during sleep, causing periods of apnea or hypopnea that often requires the patient (unbeknownst to them) to wake briefly to catch their breath. It is a quite common disorder, with up to 15-30% of males and 10-15% of females in North America carrying the diagnosis. Risk factors include male gender, obesity, smoking, craniofacial abnormalities, and older age. 

The first step for an anesthesia provider in the pre-operative period is to ascertain whether a patient carries a diagnosis of OSA, and if they do not, if they have risk factors for the disorder. If the patient carries an OSA diagnosis and has therefore had a sleep study (which is the gold standard for diagnosis), then the results of that study should be read by the anesthesia provider. Severity of OSA is classified by the apnea-hypopnea index (AHI), which is a scale based on the number of apneic or hypopneic episodes per hour of sleep. Less than 5 events indicates no OSA, 5-15 events is mild, 15-30 is moderate, and greater than 30 is severe. The more severe the disease, the more at risk a patient is both for perioperative morbidity, as well as long-term sequelae of the disease. If a patient is not diagnosed with OSA, there are a number of assessments that can be used to indicate risk. The best combination of sensitivity and specificity is the STOP-BANG questionnaire, which includes a variety of questions (snoring, daytime sleepiness, observed awakenings sleep partner, etc.). There are seven total questions, and a confirmatory answer to three or more questions indicates a high risk of OSA. 

The most important aspect of an anesthesia provider’s pre-operative assessment and perioperative plan is being aware of the risks factors associated with long-standing or untreated OSA; these include hypertension, coronary artery disease, heart failure, arrythmias, and stroke. Patients with OSA and pulmonary disease are also at particular risk for pulmonary hypertension. As a result, in a patient with OSA, functional status is an essential part of the preoperative evaluation, and cardiac catheterization or transthoracic echocardiography may be indicated prior to surgery as well.  

Once a pre-operative assessment is complete, OSA patients have a higher risk of a number of intraoperative difficulties. OSA patients are often obese, and as a result can be difficult intravenous access, high aspiration risk, and can have difficult airways, with a particularly high risk of being difficult to mask ventilate. As a result, avoiding general anesthesia using regional techniques can and should be used when possible. However, even mild to moderate amounts of sedation can be risky in OSA patients, as they by definition have airways that obstruct quite easily. When general anesthesia is required, an RSI may be indicated depending on the patient’s weight and comorbidities, and in other circumstances an awake fiberoptic intubation may be the safest approach. 

Post-operatively, hypoventilation is the most important concern for OSA patients. Patients with OSA tend to be sensitive to narcotics, and as stated above, obstruct their airways easily. This combination can be devastating if high doses of narcotics are used, so this should be avoided during surgery and afterwards. In addition, moderate to severe OSA patients are not good candidates for same day surgery, and should be monitored in a hospital setting postoperatively until the effects of anesthesia have completely worn off. The use of CPAP in OSA patients post-operatively has been studied without clear conclusions, but positive pressure ventilation techniques should, at the least, be readily available to post-operative providers. 

References: 

Chung et al. Society of Anesthesia and Sleep Medicine Guidelines on Preoperative Screening and Assessment of Adult Patients With Obstructive Sleep Apnea. Anesth Analg. 2016 Aug;123(2):452-73. doi: 10.1213/ANE.0000000000001416. 

Okoronkwo U. Ogan, M.D.; David J. Plevak, M.D. Anesthesia Safety Always an Issue with Obstructive Sleep Apnea. APSF Newsletter. Volume 12, No. 2, 1997. 

Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328:1230. 

Sunwoo JS, Hwangbo Y, Kim WJ, et al. Prevalence, sleep characteristics, and comorbidities in a population at high risk for obstructive sleep apnea: A nationwide questionnaire study in South Korea. PLoS One 2018; 13:e0193549. 

Mason M, Cates CJ, Smith I. Effects of opioid, hypnotic and sedating medications on sleep-disordered breathing in adults with obstructive sleep apnoea. Cochrane Database Syst Rev 2015; :CD011090. 

Hormonal processes of childbearing are essential to pregnancy, labor, birth, breastfeeding and the maternal–child attachment.¹ Hormone release in both the mother and the baby is coordinated to optimize outcomes, such as maternal and fetal readiness for labor.¹ Oxytocin is a hormone that is produced naturally by the body, but also administered to induce labor that may not have started on its own² or to prevent postpartum blood loss.³ To provide the best care to their parturient patients, anesthesia providers should be familiar with the uses of oxytocin as well as protocols for oxytocin in Cesarean delivery.⁴ 

Prelabor preparation in the maternal body involves many complex hormonal and physiological changes.¹ These changes, which occur in the weeks, days and hours before the onset of labor in humans and animals, include rising estrogen levels, activating the uterus for efficient labor; increases in oxytocin and prostaglandin activity, causing cervical ripening; increased inflammation, which activates the cervix and uterus; increased uterine oxytocin receptors, allowing for effective contractions during labor and reduced bleeding after birth; increased central nervous system (CNS) receptors for beta-endorphins, contributing to endogenous analgesia in labor; and elevations in mammary and CNS oxytocin and prolactin receptors, which promote breastfeeding and maternal-infant attachment after birth.¹ Similarly, changes in hormones and neurotransmitters affect the baby’s adaptations for labor as well.¹ In some situations, such as scheduled birth, endogenous hormonal activities do not align with external needs. In these cases, clinicians will administer exogenous hormones to encourage certain processes. Once the cervix has been softened using prostaglandins, a health professional will provide a synthetic version of oxytocin (known as Pitocin) to cause uterine contraction and thus induce labor.⁵ Oxytocin is more effective at speeding up labor that has already begun than it is at beginning the labor process.⁵ When epidural analgesia is used during vaginal birth, the resulting reduction in maternal oxytocin may require the clinician to administer exogenous oxytocin to compensate.¹ Also, clinicians commonly administer oxytocin after both vaginal and operative delivery to initiate and maintain adequate uterine contractility, thus minimizing blood loss and preventing postpartum hemorrhage.³ Evidently, oxytocin and various other hormones are crucial to efficient labor, and may be administered by clinicians to provoke certain essential processes. Future research is needed to assess the long-term effects of exogenous oxytocin exposure during labor and delivery.⁶ 

Anesthesia providers are highly involved in Cesarean sections, and one of their many roles can involve oxytocin administration. Because Cesarean section is fetal birth through incisions in the abdominal wall and uterine wall, it does not involve the same endogenous hormone releases as does vaginal birth.⁷ Thus, oxytocin infusion at Cesarean section may help maintain uterine contractility throughout the procedure and immediately postpartum, when most hemorrhage (blood loss) occurs.⁷ The protocols surrounding oxytocin administration for Cesarean section are complicated and must be followed precisely.⁴ However, there remains a lack of consensus among anesthesiology practitioners regarding optimal dose and mode of administration.⁸ For example, Terblanche et al.’s review showed no conclusion for or against the effectiveness of 5IU oxytocin versus a lower dose for combatting postpartum blood loss.⁸ However, Balki et al. found that women requiring Cesarean delivery for labor arrest required approximately 3IU of intravenous oxytocin to achieve effective uterine contraction after delivery.⁹ Kovacheva et al. found that when compared to women receiving continuous infusions of oxytocin, women who received a low-dose bolus of 3IU oxytocin achieved the same adequate uterine tone while using less oxytocin.¹⁰ On the other hand, high doses of oxytocin can cause cardiovascular issues or desensitization of oxytocin receptors.¹¹ Some researchers show that timing may be an important factor in oxytocin infusion. Bhattacharya et al. found that in elective Cesarean delivery patients, bolus oxytocin of 3IU over 15 seconds and infusion of oxytocin at 3IU over five minutes had comparable uterotonic effects, but the bolus administration resulted in significantly more cardiovascular events.³ Additionally, Foley et al.’s retrospective chart review found that pre-Cesarean exposure to oxytocin led patients to require a high postpartum oxytocin infusion rate more often than patients who were not exposed.¹² Clinicians have yet to determine the optimal dose and timing of oxytocin doses in Cesarean section.¹¹ 

Anesthesia providers often care for parturient patients who are experiencing various hormonal changes. Sometimes, vaginal or Cesarean delivery requires exogenous oxytocin to induce labor or prevent postpartum blood loss. Future studies should evaluate the optimal dose of oxytocin doses, the most effective mode of administration and the possible long-term implications of oxytocin administration during Cesarean delivery.  

1.Buckley SJ. Executive Summary of Hormonal Physiology of Childbearing: Evidence and Implications for Women, Babies, and Maternity Care. The Journal of Perinatal Education. 2015;24(3):145–153. 

2.Hormone Health Network. What is Oxytocin? Glands & Hormones A–Z November 2018; https://www.hormone.org/your-health-and-hormones/glands-and-hormones-a-to-z/hormones/oxytocin. 

3.Bhattacharya S, Ghosh S, Ray D, Mallik S, Laha A. Oxytocin administration during cesarean delivery: Randomized controlled trial to compare intravenous bolus with intravenous infusion regimen. Journal of Anaesthesiology, Clinical Pharmacology. 2013;29(1):32–35. 

4.Balki M, Tsen L. Oxytocin protocols for Cesarean delivery. International Anesthesiology Clinics. 2014;52(2):48–66. 

5.Mayo Clinic. Labor induction. Tests & Procedures September 11, 2017; https://www.mayoclinic.org/tests-procedures/labor-induction/about/pac-20385141. 

6.Erickson EN, Emeis CL. Breastfeeding Outcomes After Oxytocin Use During Childbirth: An Integrative Review. Journal of Midwifery & Women’s Health. 2017;62(4):397–417. 

7.Abbas AM. Oxytocin Administration During Cesarean Section. ClinicalTrials.gov: U.S. National Library of Medicine; April 23, 2018. 

8.Terblanche NCS, Picone DS, Otahal P, Sharman JE. Paucity of evidence for the effectiveness of prophylactic low-dose oxytocin protocols (<5 IU) compared with 5 IU in women undergoing elective caesarean section: A systematic review of randomised controlled trials. European Journal of Anaesthesiology. 2018;35(12):987–989. 

9.Balki M, Ronayne M, Davies S, et al. Minimum Oxytocin Dose Requirement After Cesarean Delivery for Labor Arrest. Obstetrics & Gynecology. 2006;107(1):45–50. 

10.Kovacheva VP, Soens MA, Tsen LC. A Randomized, Double-blinded Trial of a “Rule of Threes” Algorithm versus Continuous Infusion of Oxytocin during Elective Cesarean Delivery. Anesthesiology: The Journal of the American Society of Anesthesiologists. 2015;123(1):92–100. 

11.Yamaguchi ET, Siaulys MM, Torres MLA. Oxytocin in cesarean-sections. What’s new? Brazilian Journal of Anesthesiology (English Edition). 2016;66(4):402–407. 

12.Foley A, Gunter A, Nunes KJ, Shahul S, Scavone BM. Patients Undergoing Cesarean Delivery After Exposure to Oxytocin During Labor Require Higher Postpartum Oxytocin Doses. Anesthesia and Analgesia. 2018;126(3):920–924. 

Globalization has connected people, markets and governments all over the world; thus, health policy has become an international issue.¹ This includes promoting health across borders and assisting countries in assessing and acting on international public health risks.¹ Global health initiatives range from non-governmental organizations² to governmental institutions³ to humanitarian programs such as Médecins Sans Frontières (Doctors Without Borders).⁴ As clinicians who are crucial to pain management and surgical procedures, anesthesia providers should be familiar with global health issues and associated organizations, types of global health efforts and anesthesiology professionals’ roles in global health care. 

Global health issues change constantly depending on patterns of infectious diseases, humanitarian crises or environmental factors.⁵ According to the World Health Organization (WHO), ten of the main global health issues in 2019 were air pollution and climate change, noncommunicable diseases such as diabetes and cancer, the global influenza pandemic, places with little access to health care, antimicrobial resistance from medication overuse, Ebola and other high-threat pathogens, weak primary health care, vaccine refusal, dengue fever and HIV.⁵ The WHO has a five-year plan with three main “billion” targets: one billion more people to benefit from universal health coverage, one billion more people better protected from health emergencies and one billion more people enjoying better health and well-being.⁶ Nongovernmental organizations (NGOs) working in global health include international organizations, such as the Joint United Nations Programme on HIV/AIDS (UNAIDS), the World Bank and the World Health Organization; scientific organizations such as the American Society of Tropical Medicine and Hygiene (ASTMH), the Consortium of Universities for Global Health (CUGH), the International Society for Infectious Diseases (ISID) and the International Diabetes Federation (IDF); advocacy/policy organizations such as the Earth Institute or the Global Alliance for Chronic Diseases (GACD); foundations such as the Bill and Melinda Gates Foundation and UN Foundation (UNF); and resources such as the Institute for Health Metrics and Evaluation (IMHE) and Worldmapper.⁷ 

Global health efforts often aim to improve health outcomes in low- and middle-income countries (LMICs) by strengthening health systems, which entails global investment and national intervention.⁸ At the national level, health systems improvement involves increasing capacity to manage and deliver services, situating interventions firmly within national strategies, ensuring effective implementation and coordinating external support with local resources.⁸ Countries have been collaborating to tackle health issues with specific interventions for centuries.⁹ For example, in the mid-1800s, several countries negotiated international agreements on how to combat cross-border outbreaks of diseases such as cholera and yellow fever.⁹ Among other historical milestones, the WHO was founded in 1948, the Alma-Ata Declaration of 1978 brought the focus of global health to primary care and the Global Fund to Fight AIDS, Tuberculosis and Malaria was established in 2002.¹⁰ Noncommunicable diseases, injuries and mental health have required more attention in contemporary global health efforts,¹¹ which include medical and non-medical work in the field for expatriates¹² and in-country policy changes.¹¹ 

Anesthesia providers play a crucial role in global health efforts.¹³ Surgical disease is an important cause of death and disability in LMICs; however, there remains a shortage of trained anesthesia providers in LMICs who can respond to the need for surgical care.¹³ In today’s highly connected world, application- and technology-based health solutions may expand surgical services, improve patient care and increase patient education within anesthesiology.¹⁴ Anesthesiology practitioners may focus on teaching and providing anesthesia care in a country’s teaching hospitals¹⁵ or contribute to life-supporting care during disaster management.¹⁶ Though improvements in anesthesiology are vital to global health efforts, the relationship between global health and anesthesia care remains ill-defined and unappreciated.¹⁷ Global health education in anesthesiology residency is inconsistent in program structure, goals, curricula and funding.¹⁸ In the future, outreach programs for anesthesiology residents or fellows may allow them to explore global health work and reduce the work-related barriers associated with global health care participation.¹⁹ 

As people all over the world connect through technology and travel, international health systems improvement becomes a main focus of health care efforts. Global health challenges cross borders and are constantly changing, with organizations targeting a variety of diseases and environmental issues throughout different regions. As the need for surgery rises, anesthesia providers become more vital to global health efforts. In the future, anesthesiology professionals should investigate global health curricula and opportunities for anesthesia providers to participate in global health work. 

1.Drager N, Beaglehole R. Globalization: Changing the public health landscape. Bulletin of the World Health Organization. 2001;79(9):803. 

2.Delisle H, Roberts JH, Munro M, Jones L, Gyorkos TW. The role of NGOs in global health research for development. Health Research Policy and Systems. 2005;3(1):3. 

3.National Institutes of Health (NIH) Fogarty International Center. Global Health at NIH. Global Health Resources March 2020; https://www.fic.nih.gov/Global/Global-Health-NIH/Pages/default.aspx. 

4.Médecins Sans Frontières/Doctors Without Borders. 2020; https://www.doctorswithoutborders.org/. 

5.World Health Organization. Ten threats to global health in 2019. Feature stories 2019; https://www.who.int/news-room/feature-stories/ten-threats-to-global-health-in-2019. 

6.Thirteenth general programme of work 2019−2023. Geneva, Switzerland: World Health Organization; May 16, 2018. 

7.National Institutes of Health (NIH) Fogarty International Center. Nongovernmental Organizations (NGOs) Working in Global Health Research. Global Health Resources August 2019; https://www.fic.nih.gov/Global/Global-Health-NIH/Pages/default.aspx. 

8.Balabanova D, McKee M, Mills A, Walt G, Haines A. What can global health institutions do to help strengthen health systems in low income countries? Health Research Policy and Systems. 2010;8(1):22. 

9.Fidler DP. The globalization of public health: The first 100 years of international health diplomacy. Bulletin of the World Health Organization. 2001;79:842–849. 

10.The U.S. Government Engagement in Global Health: A Primer. San Francisco: Kaiser Family Foundation; February 5, 2019. 

11.De Cock KM, Simone PM, Davison V, Slutsker L. The new global health. Emerging Infectious Diseases. 2013;19(8):1192–1197. 

12.Work in the field. Médecins Sans Frontières/Doctors Without Borders 2020; https://www.doctorswithoutborders.org/careers/work-field. 

13.Klar G. The Role of Anesthesiology in Global Health: A Comprehensive Guide. Canadian Journal of Anesthesia/Journal canadien d’anesthésie. 2015;62(8):941. 

14.Atcheson CLH. The Future of Anesthesiology and Global Health in a Connected World. In: Roth R, Frost EAM, Gevirtz C, Atcheson CLH, eds. The Role of Anesthesiology in Global Health: A Comprehensive Guide. Cham: Springer International Publishing; 2015:403–416. 

15.Bridenbaugh PO. Role of Anesthesiologists in Global Health: Can One Volunteer Make a Difference? International Anesthesiology Clinics. 2010;48(2):165–175. 

16.Chandler D, Keflemariam Y, Fox CJ, Kaye AD. Anesthesiologists’ Role in Disaster Management. In: Roth R, Frost EAM, Gevirtz C, Atcheson CLH, eds. The Role of Anesthesiology in Global Health: A Comprehensive Guide. Cham: Springer International Publishing; 2015:305–321. 

17.Harris MJ. We Need More Reports of Global Health Anesthesia Articles. Anesthesiology: The Journal of the American Society of Anesthesiologists. 2016;124(2):267–269. 

18.Kaur G, Tabaie S, Brar J, Tangel V, Pryor KO. Global health education in United States anesthesiology residency programs: A survey of resident opportunities and program director attitudes. BMC Medical Education. 2017;17(1):215. 

19.McCunn M, Speck RM, Chung I, Atkins JH, Raiten JM, Fleisher LA. Global health outreach during anesthesiology residency in the United States: A survey of interest, barriers to participation, and proposed solutions. Journal of Clinical Anesthesia. 2012;24(1):38–43. 

Pregnancy termination can be a complicated procedure for both the patient and the provider. Patients may have different preferences for anesthesia or sedation,¹ and providers may have to alter the procedure depending on the patient’s gestational age.² During the first trimester, an abortion procedure can be completed with manual vacuum aspiration (MVA) or electric vacuum aspiration.³ Later procedures may require dilation and evacuation (D&E) or dilation and extraction (D&X), which involve hours to days of cervical preparation and widening.^2,4 The pre-abortion process entails counseling, paperwork, a thorough medical history, physical examination, blood test, screening for sexually transmitted infections and an ultrasound to confirm the age of the pregnancy.² During the procedure, anesthesia and analgesia may consist of local anesthesia and analgesic or sedative medications.⁵ Anesthesiology professionals and abortion providers should be aware of the variety of medications used for pregnancy termination procedures, as well as the efficacy of certain medications and practices.

Because pregnancy termination is a relatively routine procedure, most abortions can be performed on an outpatient basis.⁶ Thus, an anesthesiologist may not always be necessary. Instead, nurses and nurse practitioners who have special training in abortion procedures may administer local anesthesia and moderate sedation.⁶ The type of provider who administers anesthesia or sedation and the type of medication used may differ across clinics and based on gestational age.⁷ For example, most providers give patients oral pain medication, such as ibuprofen, before the procedure in order to prevent pain.^5-7 In some practices, oral medication may include a sedative, such as a benzodiazepine (e.g., Valium) or a stronger pain medication, such as an opioid (e.g., Vicodin).⁶ Also, some patients may request intravenous mild, moderate or heavy sedation to reduce anxiety and pain during the procedure.⁸ Moderate sedation will allow the patient to stay awake but very relaxed, while heavy sedation means complete loss of consciousness.⁷ In addition to these anesthetic and analgesic medications, the patient will receive antibiotics to reduce risk of infection, as well as medications to soften the cervix depending on gestational age.⁸ Guidelines for eating or drinking before a procedure vary based on gestational age and clinic practices, including use of anesthetics. While some procedures do not require fasting before the appointment,^6,7 others may entail foregoing food for several hours in preparation for heavy sedation.⁸ Overall, anesthetic practices for pregnancy termination depend on procedure type, gestational age and the preferences of both the patient and provider.

Due to these various factors, the efficacy of anesthetic techniques varies widely between patients. For abortion procedures without intravenous medications, Allen and Singh recommend a multimodal approach to pain management, such as premedication with a non-steroidal anti-inflammatory drug (NSAID), emotional support person, visual or auditory distraction and local anesthesia to the cervix with lidocaine.⁹ According to their review, oral opioids did not reduce procedural pain and oral anxiolytics decreased anxiety (but not pain) in patients who did not use intravenous anesthesia.⁹ In their study, Hamoda et al. found that MVA under local anesthesia was effective and acceptable to patients.¹⁰ Meanwhile, a study by Xia and Chen found that local anesthesia combined with psychological intervention was more effective in pain relief and patient satisfaction than local anesthesia alone, suggesting that nonpharmacological interventions may be useful in cases without intravenous sedation.¹¹ Other research has approached intravenous medications for patients who necessitate or request it. Rawling and Wiebe’s study found that intravenous fentanyl was not significantly effective in pain reduction compared to placebo.¹² Zhang et al. showed that intravenous propofol and dezocine led to more pain reduction and shorter recovery time than propofol alone.¹³ In regards to complications, Clare et al. found that inhaled sevoflurane or desflurane led to greater intraoperative blood loss than intravenous propofol.¹⁴ Another study by Gokhale et al. found that intravenous sedation with fentanyl without tracheal intubation did not increase risk of complications in obese patients compared to non-obese patients.¹⁵ Evidently, a variety of intravenous, inhaled and oral medications can be used to induce different levels of anesthesia.

Anesthesia provision for pregnancy termination is complex, as it depends on gestational age, patient and provider preferences and institutional practices. Analgesia and anesthesia in abortion can range from no sedation to complete loss of consciousness, and can be provided through oral, intravenous or inhaled routes. Future research is needed to evaluate the best forms of pharmacologic and nonpharmacologic pain control in patients who do not use moderate or heavy sedation.⁹ Additionally, policies should aim to standardize care across clinics in order to effectively assess different anesthetic practices for pregnancy termination.

1.         Singh R. Patient Preferences in Anesthesia for Abortion Care (PAC). ClinicalTrials.gov October 26, 2017.

2.         Johnson TC. What Are the Types of Abortion Procedures? Women’s Health March 30, 2019; https://www.webmd.com/women/abortion-procedures.

3.         Goldberg AB, Dean G, Kang MS, Youssof S, Darney PD. Manual versus electric vacuum aspiration for early first-trimester abortion: A controlled study of complication rates. Obstetrics & Gynecology. 2004;103(1):101–107.

4.         Blanchard K, Fried MG, Issokson D, et al. Dilation and Evacuation Abortion. Abortion April 2, 2014; https://www.ourbodiesourselves.org/book-excerpts/health-article/dilation-and-evacuation-abortion/.

5.         Sharma M. Manual vacuum aspiration: An outpatient alternative for surgical management of miscarriage. The Obstetrician & Gynaecologist. 2015;17(3):157–161.

6.         UCSF Health. Surgical Abortion (First Trimester). In: The Regents of the University of California, ed. Treatments A–Z. Web 2020.

7.         Planned Parenthood Federation of America. What happens during an in-clinic abortion? In-Clinic Abortion 2020; https://www.plannedparenthood.org/learn/abortion/in-clinic-abortion-procedures/what-happens-during-an-in-clinic-abortion.

8.         UCSF Health. Surgical Abortion (Second Trimester). In: The Regents of the University of California, ed. Treatments A–Z. Web 2020.

9.         Allen RH, Singh R. Society of Family Planning clinical guidelines pain control in surgical abortion part 1—Local anesthesia and minimal sedation. Contraception. 2018;97(6):471–477.

10.       Hamoda H, Flett GM, Ashok PW, Templeton A. Surgical abortion using manual vacuum aspiration under local anaesthesia: A pilot study of feasibility and women’s acceptability. The Journal of Family Planning and Reproductive Health Care. 2005;31(3):185–188.

11.       Xia L, Chen Y. Effect of lidocaine combined with local anesthesia and psychological intervention on induced abortion. Chinese Journal of Biochemical Pharmaceutics. 2017;37(6):351–352.

12.       Rawling MJ, Wiebe ER. A randomized controlled trial of fentanyl for abortion pain. American Journal of Obstetrics & Gynecology. 2001;185(1):103–107.

13.       Zhang M, Ying C, Wei H. Evaluation of different doses dezocine combined with propofol intravenous anesthesia for artificial abortion. Chinese Journal of Primary Medicine and Pharmacy. 2016;23(12):1824–1827.

14.       Clare CA, Hatton GE, Shrestha N, et al. Intraoperative Blood Loss during Induced Abortion: A Comparison of Anesthetics. Anesthesiology Research and Practice. December 2, 2018;2018:5.

15.       Gokhale P, Lappen JR, Waters JH, Perriera LK. Intravenous Sedation Without Intubation and the Risk of Anesthesia Complications for Obese and Non-Obese Women Undergoing Surgical Abortion: A Retrospective Cohort Study. Anesthesia & Analgesia. 2016;122(6):1957–1962.

Oxycodone is a semisynthetic opioid drug with analgesic properties.¹ Oxycodone is manufactured by modifying the chemical thebaine, an organic chemical found in opium.² It is the active ingredient in prescription pain medications such as Percocet, Percodan, Tylox and OxyContin, which are formulated through combinations with other pain relievers such as aspirin.¹ Oxycodone was first developed in Germany in 1916, and it first came to the United States in 1939.³ In 1996, when Purdue Pharma began manufacturing OxyContin in the U.S., oxycodone became more widely used (and abused).³ Because oxycodone is an active ingredient in several pain medications, anesthesia providers should have thorough knowledge of its biological mechanisms, clinical applications and side effects.

The molecular formula for oxycodone is C₁₈H₂₁NO₄.⁴ Oxycodone is a μ-opioid and κ-opioid receptor agonist.⁵ Through binding at both of these receptors, oxycodone inhibits neuronal activity⁴ and exhibits antinociceptive (i.e., pain-relieving) effects.⁵ It binds to areas in the cortex and other regions that have effects not relating to analgesia, such as the respiratory center in the brainstem, cough center in the medulla oblongata, muscles of the pupils, gastrointestinal tract, cardiovascular system, endocrine system and immune system.⁴ The lipid solubility of oxycodone is similar to that of morphine, and protein binding is low (i.e., 38 percent to 45 percent).⁵ Oxycodone’s duration of action depends on its formulation, ranging from three to four hours to 12 hours.⁶ Because it undergoes low first-pass metabolism, the oral bioavailability of oxycodone is better than morphine, ranging from 60 to 87 percent.⁷ Thus, it is almost twice as potent as morphine.⁸ It is metabolized mainly in the liver by CYP3A4 and CYP2D6 enzymes to the active metabolite oxymorphone, which is three times more potent than morphine.⁷ Another metabolite of oxycodone is noroxycodone, which has weak µ-opioid receptor activity compared with oxycodone or oxymorphone.⁷ Oxycodone and its metabolites are excreted in the urine, with less than 10 percent of oxycodone excreted unchanged.⁷ Women eliminate oxycodone 25 percent more slowly than do men.⁵ Overall, oxycodone and its metabolites exert analgesic effects through actions on opioid receptors.

Oxycodone can be used in a variety of clinical settings. Oxycodone products can be administered intramuscularly, intravenously, subcutaneously, rectally or orally through pills and tablets.⁹ Parenteral (i.e., not oral) oxycodone is not available in the United States.¹⁰ In the U.S., oxycodone is currently used in a controlled-release preparation for cancer-related and chronic non-malignant pain, as well as in an immediate-release preparation for acute or breakthrough pain.¹¹ Its immediate and sustained-release formulations make it useful for moderate to severe postoperative pain.¹² In other countries, intravenous oxycodone can be administered during the preoperative period to induce sedation and prevent perioperative pain.¹³ Oxycodone has clinical uses that are similar to those of other opioid drugs; however, its parenteral applications are not available in the U.S.

The side effects of oxycodone are similar to those of other opioids.⁵ Oxycodone may cause drowsiness, confusion, lightheadedness, nausea, vomiting, pruritus (itching), sweating, urinary retention and constipation.¹⁴ The incidence of constipation is more than with morphine, but there is a relatively decreased incidence of nausea.⁵ More severe consequences of oxycodone use may include changes in pulse, respiration and blood pressure; seizures; pupil constriction; loss of consciousness; or coma and/or death.^14,15 Compared to other opioid drugs, oxycodone has an increased potential for abuse and dependence.¹⁶ Drugs made from oxycodone, such as OxyContin, can be crushed up and used intranasally or intravenously to achieve a “high.”¹⁷ Providers should be careful when prescribing oxycodone given the addictive properties, adverse effects and overdose potential of oxycodone-containing formulations.

Oxycodone is a semisynthetic analgesic drug that acts as a μ-opioid and κ-opioid receptor agonist, thus inhibiting the body’s sense of pain. The metabolism of oxycodone in the liver creates active metabolites, which have an additional analgesic effect. Oxycodone is available in immediate-release and long-acting formulations, giving it clinical applications that include both acute and chronic pain. The side effects of oxycodone, such as drowsiness, nausea, vomiting, itching, sweating and constipation, are similar to those of other opioid drugs. Oxycodone overdose can have severe consequences such as respiratory depression and death. Due to the widespread abuse of oxycodone-based drugs such as OxyContin, anesthesia providers should carefully consider prescribing oxycodone.

1.         Center for Substance Abuse Research. Oxycodone. University of Maryland October 29, 2013; http://www.cesar.umd.edu/cesar/drugs/oxycodone.asp.

2.         Lipp A, Ferenc D, Gütz C, et al. A Regio- and Diastereoselective Anodic Aryl–Aryl Coupling in the Biomimetic Total Synthesis of (−)-Thebaine. Angewandte Chemie International Edition. 2018;57(34):11055–11059.

3.         Winkel B. The History of OxyContin. Treatment Solutions January 9, 2010; https://www.treatmentsolutions.com/blog/the-history-of-oxycontin/.

4.         Oxycodone. DrugBank February 17, 2020; https://www.drugbank.ca/drugs/DB00497.

5.         Koyyalagunta D. Chapter 113—Opioid Analgesics. In: Waldman SD, Bloch JI, eds. Pain Management. Philadelphia: W.B. Saunders; 2007:939–964.

6.         Ordóñez Gallego A, González Barón M, Espinosa Arranz E. Oxycodone: A pharmacological and clinical review. Clinical & Translational Oncology. 2007;9(5):298–307.

7.         Sindt JE, Jenkinson RH. Nonintravenous Opioids. In: Hemmings HC, Egan TD, eds. Pharmacology and Physiology for Anesthesia (Second Edition). Philadelphia: Elsevier; 2019:354–368.

8.         Cortazzo MH, Copenhaver D, Fishman SM. Major Opioids and Chronic Opioid Therapy. In: Benzon HT, Rathmell JP, Wu CL, Turk DC, Argoff CE, Hurley RW, eds. Practical Management of Pain (Fifth Edition). Philadelphia: Mosby; 2014:495–507.e493.

9.         Pöyhiä R, Vainio A, Kalso E. A review of oxycodone’s clinical pharmacokinetics and pharmacodynamics. Journal of Pain and Symptom Management. 1993;8(2):63–67.

10.       Stoops WW, Hatton KW, Lofwall MR, Nuzzo PA, Walsh SL. Intravenous oxycodone, hydrocodone, and morphine in recreational opioid users: Abuse potential and relative potencies. Psychopharmacology. 2010;212(2):193–203.

11.       Lee MC, Abrahams M. Chapter 18—Pain and analgesics. In: Bennett PN, Brown MJ, Sharma P, eds. Clinical Pharmacology (Eleventh Edition). Oxford: Churchill Livingstone; 2012:278–294.

12.       Sharav Y, Benoliel R. Pharmacotherapy of acute orofacial pain. In: Sharav Y, Benoliel R, eds. Orofacial Pain and Headache. Edinburgh: Mosby; 2008:349–376.

13.       Wang J, Fu Y, Ma H, Wang N. Effect of Preoperative Intravenous Oxycodone After Transurethral Resection of Prostate Under General Anesthesia. International Surgery. 2018;102(7–8):377–381.

14.       Mayo Clinic. Oxycodone (Oral Route). Drugs & Supplements February 1, 2020; https://www.mayoclinic.org/drugs-supplements/oxycodone-oral-route/side-effects/drg-20074193.

15.       Oxycodone. PubChem Database. Web: National Center for Biotechnology Information; 2020.

16.       Resnik RR. Postoperative Complications. In: Resnik RR, Misch CE, eds. Misch’s Avoiding Complications in Oral Implantology: Mosby; 2018:364–401.

17.       Lofwall MR, Moody DE, Fang WB, Nuzzo PA, Walsh SL. Pharmacokinetics of intranasal crushed OxyContin and intravenous oxycodone in nondependent prescription opioid abusers. Journal of Clinical Pharmacology. 2012;52(4):600–606.

Fentanyl is a synthetic opioid drug that is 50 to 100 times more potent than morphine and exhibits vastly different properties and pharmacokinetics.¹ The Belgian pharmaceutical company Janssen Pharmaceutica first developed fentanyl in 1959.² In the 1960s, fentanyl was introduced into medical practice as an anesthetic agent, and is now used for both anesthesia and analgesia.² Fentanyl is classified as a United States Drug Enforcement Administration (DEA) Schedule II drug, which means that it has “a high potential for abuse, with use potentially leading to severe psychological or physical dependence.”³ In December 2018, the Centers for Disease Control and Prevention (CDC) pronounced fentanyl the deadliest drug in America due to its potency, addictive properties and role in the opioid crisis.⁴ Because of fentanyl’s potential to cause rapid death, anesthesia providers should understand its biological mechanisms, surgical applications and side effects.⁴

The molecular formula for fentanyl, also known as fentanyl citrate, is C₂₂H₂₈N₂O.⁵ Fentanyl is lipophilic, meaning that it tends to spread to fatty tissues and thus has greater bioavailability than hydrophilic (water-soluble) drugs.⁵ Like other opioids, fentanyl binds to the m-opioid receptor in the central nervous system (CNS), thus reducing neuronal excitability.⁵ However, fentanyl also serves as an agonist for other opioid receptors such as the delta and kappa receptors.¹ Activation of these opioid receptors produces analgesia, while increases in the release of dopamine elicits exhilaration and relaxation effects.¹ Fentanyl is metabolized extensively in the liver and intestines via the enzyme CYP3A4.⁵ Less than 11 percent of the dose is excreted through urine and feces as inactive metabolites or as unchanged drug.⁵ Fentanyl metabolism, elimination and duration of effects may be affected by medications or substances that inhibit the CYP3A4 enzyme.⁶

Fentanyl comes in several forms, which allow it to serve a variety of purposes.⁷ When used to treat breakthrough pain for patients who use opioids on a long-term basis, fentanyl comes as a lozenge on a handle, a sublingual tablet, a film and a buccal tablet.⁷ Fentanyl is also administered intravenously, intramuscularly, transdermally as skin patches, intranasally via a nasal spray and intrathecally.¹ In contrast to other opioid drugs, fentanyl is less common as an oral tablet or powder.¹ For surgical procedures, fentanyl can be used preoperatively, during surgery and in the immediate postoperative period.⁵ Before surgery, fentanyl provides anxiolysis and relaxation.⁵ In combination with other anesthetic drugs, fentanyl is useful for procedures that require patients to be lightly anesthetized or awake.⁵ However, it may be administered with oxygen and a muscle relaxant to provide anesthesia without the use of additional anesthetic agents.⁵ Fentanyl can prevent or relieve postoperative emergence delirium.⁵ Clearly, fentanyl has various uses as an analgesic and anesthetic drug.

Unfortunately, fentanyl’s many uses are accompanied by many side effects. Fentanyl’s side effects are similar to those of heroin, including euphoria, confusion, drowsiness, nausea, visual disturbances or hallucinations, delirium and constipation.¹ Serious adverse effects include addiction, hypotension, coma, respiratory depression and death.¹ Fentanyl and its derivatives can produce rigidity in the diaphragm, chest wall and upper airway—known as “wooden chest syndrome” (WCS)—within a narrow dosing range.⁴ WCS can be fatal and causes rapid death without proper airway management.⁴ Because fentanyl is so potent and overdose is likely, anesthesia providers must be extremely diligent when providing patients with fentanyl.⁸ Patients who have respiratory issues or liver failure or who are using drugs such as alcohol, antibiotics or antifungal agents may not be able to use fentanyl.¹ Fentanyl can be habit forming, so patients should be educated about its proper use and addictive properties.⁷

Fentanyl is an extremely potent synthetic opioid that is used for analgesia and anesthesia. By activating certain opioid receptors, fentanyl inhibits neuronal activity. Fentanyl is primarily used for analgesia in combination with other anesthetics. Fentanyl’s side effects range from drowsiness and nausea to coma, respiratory depression and even death. Because fentanyl is a highly addictive substance, anesthesiology professionals should prescribe it cautiously.

1.         Ramos-Matos CF, Lopez-Ojeda W. Fentanyl. StatPearls. Web: StatPearls Publishing LLC; October 3, 2019.

2.         Dale E, Ashby F, Seelam K. Report of a patient chewing fentanyl patches who was titrated onto methadone. BMJ Case Reports. 2009;2009:bcr01.2009.1454.

3.         United States Drug Enforcement Administration. Drug Scheduling. Drug Information 2020; https://www.dea.gov/drug-scheduling.

4.         Torralva R, Janowsky A. Noradrenergic Mechanisms in Fentanyl-Mediated Rapid Death Explain Failure of Naloxone in the Opioid Crisis. Journal of Pharmacology and Experimental Therapeutics. 2019;371(2):453–475.

5.         Fentanyl. PubChem Database. Web: National Center for Biotechnology Information; 2020.

6.         Kharasch ED, Whittington D, Hoffer C. Influence of hepatic and intestinal cytochrome P4503A activity on the acute disposition and effects of oral transmucosal fentanyl citrate. Anesthesiology. 2004;101(3):729–737.

7.         Fentanyl. MedlinePlus. Bethesda, MD: National Institutes of Health; October 15, 2019.

8.         Simmons B, Kuo A. 40—Analgesics, Tranquilizers, and Sedatives. In: Brown DL, ed. Cardiac Intensive Care (Third Edition). Philadelphia: Elsevier; 2019:421–431.e425.

Humans have used herbs and plants for medicinal purposes since ancient times.¹ The oldest written evidence of medicinal plants’ usage for drug preparation is on a 5000-year-old Sumerian clay slab from Nagpur.¹ It includes 12 recipes for drug preparation with over 250 various plants, including poppy, henbane, and mandrake.¹ These plants contain pharmacologically active components that can treat illness.¹ Today, herbal medicines’ therapeutic potential should not be dismissed, given the long history of their successful use.² Herbal products may also interfere with other contemporary medicines, so medical providers must be aware of their potential effects and mechanisms of action.² Anesthesia providers in particular should be aware of commonly used herbal supplements and their functions, as well as their potential to affect anesthetic drugs.

Herbal products, also known as dietary supplements, alternative therapies, complementary medicine and homeopathic or holistic health care, are common in many societies.³ According to the World Health Organization (WHO), up to 80 percent of the world’s population still depends on herbal medicines.⁴ Patient surveys have reported that 12 percent of Americans, 12 percent of Australians, and 4.8 percent of patients in the UK use herbal remedies.⁴ Commonly used compounds include feverfew, garlic, ginseng, ginkgo, St. John’s wort, hoodia, kava, valerian and echinacea.^3,5 Because the United States Food and Drug Administration (FDA) considers these pharmacologically active agents as foods or supplements, they are not subject to standard drug regulations.² There are limited instructions on proper use, dosage requirements, possible side effects, toxicity and drug interactions.³ Also, a lack of pharmacokinetic and pharmacodynamic data on herbal products makes it difficult to predict a patient’s reaction to the product or know if the product has any therapeutic value.⁴ Due to unstandardized dosage policies and unclear pharmacological effects, herbal supplements can be harmful to patients whether or not they are taking other medications.

Because of the possible interference with anesthetic medications, the American Society of Anesthesiologists recommends that patients discontinue the use of herbal supplements two to three weeks before surgery.⁴ However, patients are often unaware of this recommendation or in need of emergency surgery, in which case preoperative preparation time is limited.⁴ According to a study by Levy et al., 44 percent of patients hospitalized for surgery reported dietary and herbal supplement use, with 16.5 percent using substances that could potentially interact with anesthesia.⁶ In a separate study, Kaye et al. found that among 1,017 patients surveyed before outpatient anesthetic administration, 482 were using at least one herbal supplement.⁷ Despite some of the benefits of these supplements, they can negatively impact postoperative analgesia, bleeding and level of sedation.² Wong et al.’s review thoroughly describes the medicinal uses, pharmacological effects and potential anesthetic interactions of several common herbal supplements.⁴ Garlic, ginger, gingko and ginseng contribute to intraoperative risk of bleeding; kava, St. John’s wort and valerian have sedative effects and may reduce anesthetic requirements; ephedra causes sympathetic nervous system issues and arrhythmia; and echinacea can cause liver failure when combined with hepatotoxic drugs.⁴ Despite the potential perioperative dangers of these drugs on their own or in combination with anesthetic agents,³ documentation and identification of herbal remedies in medical records remain subpar. For example, in Levy et al.’s study, supplement use was only documented in 11 percent of the medical files of patients who used them.⁶ It is the anesthesia provider’s duty to ask patients open-ended questions about their herbal supplement use during the preoperative assessment.⁸ Adequate reporting of patient use and proper understanding of herbal supplement pharmacology are key to an anesthesia provider’s practice.⁸

Medicinal herbs have been used for thousands of years, and many herbs contribute to the pharmacological effects of modern-day medications. Despite their widespread use, herbal supplements are not heavily regulated and may pose dangers to patients, whether or not they use other medicines. Anesthesia providers should consider the pharmacology and possible perioperative effects of these supplements. Ideally, the anesthesia provider should ensure the patient’s discontinuation of such products well before surgery.⁴ Future research should investigate the possible uses of herbal supplements for anesthesia and analgesia to aim for a more symbiotic relationship between herbal supplements and allopathic medicine.  

1.         Petrovska BB. Historical review of medicinal plants’ usage. Pharmacognosy Reviews. 2012;6(11):1–5.

2.         Abe A, Kaye AD, Gritsenko K, Urman RD, Kaye AM. Perioperative analgesia and the effects of dietary supplements. Best Practice & Research Clinical Anaesthesiology. 2014;28(2):183–189.

3.         American Society of Nurse Anesthetists. Herbal Products and Your Anesthesia. Patients 2019; https://www.aana.com/patients/herbal-products-and-your-anesthesia.

4.         Wong A, Townley SA. Herbal medicines and anaesthesia. Continuing Education in Anaesthesia Critical Care & Pain. 2010;11(1):14–17.

5.         Skinner CM, Rangasami J. Preoperative use of herbal medicines: A patient survey. BJA: British Journal of Anaesthesia. 2002;89(5):792–795.

6.         Levy I, Attias S, Ben-Arye E, et al. Perioperative Risks of Dietary and Herbal Supplements. World Journal of Surgery. 2017;41(4):927–934.

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