INTRODUCTION:

Fentanyl is a phenylpiperidine derivative and a synthetic opioid. Its potency is approximately 75 to 125 times more than morphine¹. It is widely used in current anaesthesia practices and pain therapy. Dr. Paul Jansen, the founder of Jansen Pharmaceutica, synthesized fentanyl in the late 1950s through experimentation with meperidine. Dr. George De Castro, an anaesthesiologist based in Brussels, conducted its initial clinical evaluation. By the early to mid-1960s, fentanyl gained significant usage in Western European nations, gradually attaining global popularity in subsequent years². The intrathecal use of opioids was first described by Nicolae Racoviceanu-Piteşt in Paris in 1901³. Pert and Snyder’s discovery of opioid receptors in 1973, followed by dorsal horn opioid receptor identification in 1977, resulted in further comprehension of intrathecal opioids. In 1976 evidence provided by Yaksh showed that opioids have a direct impact on the spinal cord to modulate nociceptive stimuli.

In 1979 a ground-breaking technique of administering morphine intrathecally in a cohort of eight patients with genitourinary malignancies was demonstrated by Wang⁴.

In current practices, various intrathecal opioids are used in conjunction with general anaesthesia and local anaesthesia⁵. Several recommendations have been made by Enhanced Recovery Programs (ERPs), one of which includes provision of adequate post operative analgesia⁶. Various adjuvants, both opioids and non-opioids, are used⁷. Provision of post-operative analgesia by using intrathecal opioids has been in use for several decades and is advantageous over intravenous (IV) administration. This is because of the greater potency and longer-lasting effects due to restricted distribution volume of cerebrospinal fluid (CSF) and the gradual diffusion within the central nervous system. When employed as a single bolus technique, intrathecal opioids reduce the need for IV opioids, aid in patient mobility, and simplify fluid management due to the absence of peripheral vasodilation. Using opioids in combination with local anaesthetic agents for neuraxial anaesthesia allows for administering lower doses of anaesthetic agents while maintaining adequate analgesia⁸. Studies have demonstrated that intrathecal administration of a combination of local anaesthetics and opioids has a synergistic analgesic effect. One explanation is that each medication targets a distinct ionic channel, collectively reducing neuronal excitability. Local anaesthetics target the axons directly, while opioids exert their effects by binding to receptors located in the spinal cord⁸. The combined inhibitory effect on the conduction of A8 and C-fibres and the ability to block responses to high and low-frequency stimulations contribute to analgesia⁸. Fentanyl has emerged as the preferred adjuvant among various opioids due to its high potency, rapid onset of action, and relatively brief duration of action. It is associated with a lower risk of respiratory depression than other opioids⁸.

MATERIALS AND METHODS:

A literature search was conducted with the search phrases: “fentanyl," “intrathecal," "uses," “anaesthesia," “pharmacology," and “side effects” on the electronic database PubMed and Google Scholar. Relevant studies conducted from 2000 to 2023 in English were identified, evaluated, and selected following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 guidelines, as illustrated in the flowchart.

RESULTS:

1. Comparison of intrathecal clonidine and fentanyl in hyperbaric bupivacaine for spinal anaesthesia and post-operative analgesia in patients undergoing lower abdominal surgeries⁹: Clonidine provided longer post-operative analgesia than fentanyl but with higher sedation. Fentanyl is a preferred when sedation is not desirable. Side effects: nausea,shivering.

2. Hemodynamic and analgesic effect of intrathecal fentanyl with bupivacaine in patients undergoing elective caesarean section; a prospective cohort study¹⁰: Analgesia duration was longer in low-dose bupivacaine fentanyl and conventional-dose bupivacaine fentanyl groups than in the bupivacaine group. Side effects: Hypotension, nausea, vomiting, pruritus, shivering.

3. Comparing the effect of adding fentanyl, sufentanil, and placebo with intrathecal bupivacaine on duration of analgesia and complications of spinal anaesthesia in patients undergoing caesarean section¹¹: Fentanyl and sufentanil had similar durations of analgesia, but fentanyl had faster recovery of motor block and subsequent ambulation. Fentanyl is the preferred opioid. Side effects: Nausea, shivering, pruritus.

4. Sequential intrathecal injection of fentanyl and hyperbaric bupivacaine at different rates: Does it make a difference? A randomized controlled trial¹²: Administering fentanyl and hyperbaric bupivacaine in a rapid sequential injection resulted in better anaesthesia and longer-lasting post-operative pain relief compared to sequential injections of both drugs at the same rate. Side effects: Hypotension, nausea, vomiting, pruritus.

5. Comparative efficacy of three adjuvant medications used in combination with intrathecal bupivacaine for caesarean section anaesthesia: a randomized, double-blind clinical trial¹³: Fentanyl had more effective neuraxial block and was associated with fewer episodes of nausea. An intravenous combination of acetaminophen, morphine, and fentanyl was equally efficient in terms of sensory block onset and sensory-motor block duration. Side effects: Nausea, vomiting, respiratory complications, hypotension, bradycardia.

6. Addition of dexmedetomidine and fentanyl to intrathecal hyperbaric bupivacaine for lower limb surgeries: a randomized, comparative study¹⁴: Both fentanyl and dexmedetomidine are safe and effective. Both drugs showed similar blockade levels and produced the same side effect profiles. Dexmedetomidine had early-onset and prolonged block. Side effects: Nausea, vomiting, hypotension, bradycardia.

7. Which administration route of fentanyl better enhances the spread of spinal anaesthesia: intravenous, intrathecal or both?¹⁵ Both spinal and systemic administration of fentanyl improved the extent of spinal anaesthesia. When spinal fentanyl was combined with intravenous fentanyl, there was a more significant increase in the cephalad spread of spinal block. Side effects: Hypotension, nausea, pruritus.

8. A randomized controlled study between fentanyl and butorphanol with low-dose intrathecal bupivacaine to facilitate early post-operative ambulation in urological procedures¹⁶: The combination of low-dose bupivacaine and fentanyl provided better early post-operative recovery. This combination is particularly beneficial for elderly patients with comorbidities. Side effects: Hypotension, nausea, vomiting, sedation, pain.

9. A comparative study of analgesic effect of intrathecal nalbuphine and fentanyl as adjuvant in lower limb orthopaedic surgery¹⁷: Onset and duration of sensory block were faster with fentanyl, and post-operative nausea and vomiting were maximum with nalbuphine group. Side effects: Nausea, vomiting, shivering, pruritus, hypotension, respiratory depression.

10. Comparison of bupivacaine plus intrathecal fentanyl and bupivacaine alone for spinal anaesthesia with intravenous dexmedetomidine sedation: a randomized, double-blind, noninferiority trial¹⁸: In patients receiving intravenous dexmedetomidine during surgery, the duration of spinal anaesthesia was longer when bupivacaine is combined with fentanyl. Side effects: Intraoperative nausea, intraoperative bradycardia, intraoperative hypotension, post-operative urinary retention, post-operative nausea, post-operative vomiting.

11. Comparative addition of dexmedetomidine and fentanyl to intrathecal bupivacaine in orthopaedic procedure in lower limbs¹⁹: Dexmedetomidine has a longer duration of sensory and motor block and longer post-operative analgesia. Nausea, vomiting, and chilling were higher in plain bupivacaine. Complete regression of motor block took the highest duration in bupivacaine dexmedetomidine group. Side effects: Nausea, chills, pruritus, hypotension, bradycardia.

12. Comparison of intrathecal clonidine and fentanyl as adjuvant to hyperbaric bupivacaine in subarachnoid block for lower limb orthopaedic surgery²⁰: Clonidine provided a more prolonged duration post-operative analgesia. However, more sedation was reported. Fentanyl is a better option when sedation is not desirable. Side effects: Bradycardia, hypotension, pruritus.

13. The effect of intrathecal bupivacaine plus dextrose 5% and fentanyl compared with bupivacaine alone on the onset and duration of analgesia in patients undergoing lower-limb orthopedic surgery²¹: Patients who received bupivacaine and fentanyl experienced significantly longer durations of anaesthesia and analgesia than those who received bupivacaine alone. Side effects: Vomiting, hypotension.

14. Use of intrathecal midazolam or fentanyl as an adjunct to spinal anaesthesia with bupivacaine for lower limb surgery: a randomised controlled study²²: Fentanyl provided a better-quality post-operative analgesia than midazolam. Side effects: Bradycardia, hypotension.

15. Comparison of intrathecal bupivacaine‑fentanyl and bupivacaine‑butorphanol combinations for joint replacement surgeries²³: Both fentanyl and butorphanol were effective. However, intrathecal bupivacaine and butorphanol combination is superior for of duration of post-operative analgesia. Side effects: Hypotension, sedation, bradycardia.

16. Comparison of nalbuphine versus fentanyl as intrathecal adjuvant to bupivacaine for orthopaedic surgeries: a randomized controlled double‑blind trial²⁴: Nalbuphine and fentanyl have a similar duration of analgesia, postoperative analgesia, and side‑effects. Nalbuphine had a delayed onset of sensory and motor block. Side effects: Hypotension, nausea, vomiting.

17. Intrathecal buprenorphine versus fentanyl as adjuvant to 0.75% ropivacaine in lower limb surgeries²⁵: Both buprenorphine and fentanyl effectively extend post-operative pain relief without causing additional duration of motor blockade. However, buprenorphine provides a longer duration of sensory block and better pain relief. Side effects: Hypotension, bradycardia, sedation, dry mouth.

18. Analgesic efficacy of intrathecal fentanyl during the period of highest analgesic demand after caesarean section, a randomized controlled study²⁶: Intrathecal fentanyl provides effective intraoperative analgesia and reduce opioid consumption. It does not increase maternal or neonatal side effects. Fentanyl is prefered if morphine is unavailable. Side effects: Nausea, vomiting, pruritus, respiratory depression.

19. Comparison of fentanyl and dexmedetomidine as intrathecal adjuvants to spinal anaesthesia for abdominal hysterectomy²⁷: Dexmedetomidine is more effective fentanyl in minimizing intraoperative pain and prolonging post-operative analgesia. Dexmedetomidine caused more hypotension and bradycardia. Side effects: Hypotension, bradycardia, shivering, pruritus.

20. Comparison of the effects of intrathecal fentanyl and intrathecal morphine on pain in elective total knee replacement surgery^28: Less analgesic requirements were noted in the fentanyl group. Side effects: Nausea, vomiting, shivering.

21. Comparison of postoperative analgesia between intrathecal fentanyl and nalbuphine in addition to bupivacaine in lower section caesarean section²⁹: Intrathecal fentanyl provided longer duration of post operative analgesia with lesser side effects. Side effects: nausea, vomiting, hypotension, bradycardia.

22. Comparison of intrathecal fentanyl and nalbuphine as an adjuvant in spinal anaesthesia in lower limb orthopaedic surgeries³⁰: Nalbuphine provided better post operative analgesia. Intrathecal fentanyl provided faster onset of sensory block, motor block but had higher incidence of side effects. Side effects: nausea, vomiting, hypotension, bradycardia.

23. Comparison intrathecal bupivacaine and fentanyl and bupivacaine and dexmedetomidine for lower abdominal surgeries³¹: Dexmedetomidine provided faster onset of both sensory and motor block, better haemodynamic stability and better haemodynamic stability. Side effects: nausea, vomiting, bradycardia, hypotension, pruritus.

24. Comparison of clonidine with fentanyl as an adjuvant in infra umbilical urological surgeries³²: Clonidine provided prolonged analgesia while fentanyl provided better haemodynamic stability and lesser side effects. Side effects: nausea, vomiting, shivering, headache, bradycardia.

25. Comparative study of fentanyl and bupivacaine versus plain bupivacaine in elective caesarean section³³: Fentanyl had similar haemodynamic profile as plain bupivacaine. Side effects: hypotension, bradycardia, nausea, vomiting, shivering.

DISCUSSION:

Structure and receptors:

Fentanyl is a lipophilic compound. It dissolves readily in organic solvents and exhibits limited solubility in water. Fentanyl exhibits affinity to the mu opioid receptor, similar to morphine, and acts as a pure agonist. The binding to mu opioid receptor occurs rapidly, with a half-life (t1/2) of approximately 2.5 minutes. It has a lower affinity for delta and kappa opioid receptors. Fentanyl may also interact with serotonin receptors, as the analgesic effects of fentanyl can be diminished by administering 5-HT₁A receptor antagonists³⁴.

Pharmacology:

Mechanism of action: When administered intrathecally, fentanyl binds to a group of G protein-coupled receptors in the dorsal horn's pre-synaptic and post-synaptic regions of Laminae I and II. It activates the receptor and the G protein-coupled potassium channels (mu and delta receptors) open, and the kappa receptor mediated calcium channels close. This results in a decrease in intracellular calcium levels³⁵. As a result, the release of inhibitory transmitters such as glutamate and substance P from pre-synaptic C fibres is reduced, thereby leading to a decrease in nociceptive transmission. This reduction in transmission primarily affects C fibre terminals, while A fibre terminals are not significantly affected. Fentanyl has a structural resemblance to local anaesthetics and exhibits local anaesthetic effects on the sensory C primary afferent nerve, contributing to its analgesic effects. Fentanyl is also thought to exert its effect by decreasing the release of gamma amino butyric acid (GABA) and glycine from dorsal horn neurons. This action is via a calcium-independent process.

Pharmacodynamics: Fentanyl acts primarily on mu receptors distributed throughout the central nervous system. This includes the brain, spinal cord, and other tissues. Due to its lipophilicity, it has significantly higher CNS penetrability compared to morphine³⁵. Initially, it was believed that fentanyl has a rapid duration of action because of its rapid metabolization. But it is primarily due to redistribution within fatty tissues rather than elimination³⁵. Approximately 8% of the fentanyl molecule in the unionised form can diffuse to the receptors in the grey matter. This is explained by the relatively high pKa of 8.4³⁵.

Pharmacokinetics: Studies by Jaffe and Rowe suggested that fentanyl exerts its action on the dorsal root horn.

Unlike morphine which is about hundred times more potent when administered intrathecally than intravenously, fentanyl exhibits a lesser difference in potency. Intrathecal fentanyl is about ten to twenty times more potent than intravenous fentanyl. In contrast to morphine which has an estimated six-hour rostral ascension rate proposed by Bromage, fentanyl is absorbed at a much faster rate from the cerebrospinal fluid at the site of administration. Studies about cerebrospinal fluid flow dynamics and clearance demonstrate that increase in drug lipid solubility, as in the case of fentanyl, the bioavailability to the spinal cord decreases since the ease with which the drug can migrate across the barrier increases. This results in rapid clearance of fentanyl to epidural fat and then into epidural venous circulation and plasma. Fentanyl administered at a dose of ten to twenty-five micrograms intrathecally has an onset of action of less than ten minutes³⁶. However, due to its rapid diffusion into non-neuronal tissue, such as myelin and epidural fat, the concentration of fentanyl in cerebrospinal fluid drops rapidly. The diffusion of intrathecally administered fentanyl into epidural space and then into the bloodstream explains its systemic effects. Fentanyl does not reach an adequate concentration in the fourth ventricle, there is a lesser chance of respiratory depression in comparison to hydrophilic opioids³⁷. Cephalad spread of fentanyl is limited demonstrating segmental analgesia. The cephalad spread is caused by numerous factors: the bulk flow of cerebrospinal fluid, pressure changes within the thorax during respiration resulting in fluctuation of pressures and, the back-and-forth movement of cerebrospinal fluid due to the brain expanding and relaxing in time with the cardiac cycle³⁷.

Metabolism:

The metabolism of fentanyl is not fully understood. Hepatic metabolism is the primary route of systemic elimination, followed by renal excretion. Among the six human P450 enzymes, P450 3A4 plays a significant role in fentanyl metabolism and leads to the formation of norfentanyl which is excreted³⁷.

Uses:

Perioperative: Perioperative use of fentanyl includes acute pain management. There is no universally accepted dosage or specific medication that can provide adequate analgesia³⁷. Fentanyl is popularly used for managing acute pain in several scenarios. Feature like rapid onset of action, short duration of action with limited rostral spread makes it favourable to extend the sensory blockade of local anaesthetic agents³⁸. Providing adequate pain management after surgery is a crucial element of post-operative care3^39,40. Intrathecal fentanyl has a "ceiling effect" when doses exceed 0.25 micrograms /kilogram. This means that higher doses of intrathecal fentanyl do not enhance intraoperative analgesia and may instead lead to increased side effects⁴¹. Intrathecal fentanyl is administered via numerous modes, which include single bolus injection, repeated observer administration, and intrathecal catheter for continuous infusion or repeated bolus injection⁴².

Day-case surgery:

At doses of 10 to 30 micrograms, it exhibits a rapid onset of action of 10 to 20 minutes and a short duration of action of 4 to 6 hours. The rapid onset and short duration of action, synergistic effect on local analgesic agents, improved block quality and post-operative analgesic effects, and lesser likelihood of causing respiratory depression makes it an ideal for day-case surgeries. Following a single bolus injection of fentanyl, it can also be employed in day-case arthroscopic surgeries in order to improve analgesia without causing an extension of hospital stay⁴³.

Obstetric practice:

Nearly 80% of elective caesarean sections worldwide utilize spinal anaesthesia⁴³. It is the preferred approach in emergency as well as in elective cases. Fentanyl is used successfully in these cases for intraoperative analgesia and reduction of nausea and vomiting. Delivery of effective post-operative analgesia after caesarean section is important for the promotion of a strong mother-infant in the early post-delivery period which is required for maternal psychological status and optimal infant development. It also enables the mother to remain mobile and actively participate in the care of the newborn⁴⁴. The addition of intrathecal fentanyl at doses ranging from 2.5 to 60 micrograms has enhanced intraoperative analgesia during caesarean section (CS). Doses of more than ten micrograms nearly eliminate intraoperative visceral pain completely. It also decreases opioid consumption during the post-operative period without an increase in maternal or neonatal side effects.

Gynaecological surgeries:

Gynaecological surgeries like abdominal hysterectomies, done under spinal anaesthesia can cause visceral pain during peritoneal traction. This can be reduced by the addition of fentanyl at a dose of 10 to 25 micrograms as an adjunct to spinal anaesthesia⁴⁴.

Major joint replacement surgeries:

Fentanyl is used at a dose of 5 to 15 micrograms for joint replacement surgeries. Effective pain management plays a pivotal role in enhancing patient comfort in orthopaedic surgeries⁴⁴.

Urological surgeries:

Fentanyl is used in a dose of 5 to 15 micrograms in urological surgeries such as trans urethral resection of prostate (TURP).

Side effects:

Pruritus:

It is the most commonly encountered adverse effect of intrathecal opioids⁴⁵. Although transient and self-limiting, it can result in patient distress and anxiety. The precise mechanism for pruritus is not fully understood. It is caused by the cephalad movement of fentanyl in the cerebrospinal fluid and then the subsequent interaction with opioid receptors in the trigeminal nucleus located in the superficial part of the medulla⁴⁵. The regions of the face supplied primarily by the trigeminal nerve are affected⁴⁶. Another mechanism is that the spinal nucleus of the trigeminal nerve has a high number of opioid receptors. Additionally, the inferior most nucleus is the ophthalmic division of the spinal sensory nucleus of the trigeminal nerve. This reinforces that pruritus tends to be concentrated in the region of the nose and upper part of the face. There are studies suggestive of an “itch centre” located in the lower medulla that includes the trigeminal nucleus. Another potential mechanism is the opioid antagonism on inhibitory neurotransmitters such as gamma-aminobutyric acid (GABA) and glycine in the central nervous system⁴⁵. Modifications in the perception of pain within the central nervous system (CNS) may also contribute to the development of pruritus caused by intrathecal fentanyl⁴⁸. Pain and pruritus are transmitted by the same unmyelinated nerve fibres (C-fibres). The release of prostaglandins (PGE1 and PGE₂) amplifies the transmission of C-fibres to the central nervous system, thereby intensifying the sensation of pruritus⁴⁴. The existing therapeutic approaches for managing pruritus induced by intrathecal fentanyl are considered inadequate⁴⁵.

Following drugs have shown some positive results in preventing pruritus:

Opioid antagonist: These drugs act by mu receptor inhibition at the medullary dorsal horn and nucleus trigeminalis. Opioid antagonists Naloxone and naltrexone and agonist-antagonist Nalbuphine are used. However, large doses of pure antagonists can cause reversal of analgesia. Nalbuphine seems to be the most effective at preventing pruritus among all other drugs. However, it has the drawback of causing drowsiness (when intravenous 40 mg bolus doses are used)⁴⁵. Even a small dose of naloxone, ranging from 40 to 80 mcg, can alleviate pruritus without reversing the analgesic effects.

Propofol: Due to its ability to depress transmission in the posterior horn of the spinal cord significantly, propofol has an antipruritic effect. 10-mg bolus followed by a 30 mg/24-hour infusion, can reduce incidence of pruritus⁴⁵.

Non-steroidal anti-inflammatory drugs: non-steroidal anti-inflammatory drugs inhibit cyclooxygenase and reducing PGE₁ and PGE₂modulate pruritus perception. Drugs used are Diclofenac and Tenoxicam⁴⁵.

Droperidol: It is a neuroleptic drug that exerts its action via reduction of excitatory effects like pruritus. Its action is also exhibited on account of its weak 5HT₃receptor antagonist action⁴⁵.

5HT₃receptor antagonist: Drugs like Ondansetron relieve pruritus via their action on the 5HT₃receptors located in the spinal tract of the trigeminal nerve in medulla oblongata⁴⁵.

Anti histaminics: H1 blockers have limited efficacy in addressing centrally-induced pruritus as there is no histamine release. First-generation H1 receptor antagonists like diphenhydramine or hydroxyzine by induction of sedation may benefit patients experiencing pruritus by interrupting the itch-scratch cycle rather than causing relief from the sensation itself⁴⁵.

Respiratory depression: The administration of opioids carries a notable risk of respiratory depression⁴⁵. When lipophilic opioids like fentanyl are employed, respiratory depression commonly manifests within the first 30 minutes, and episodes occurring beyond 2 hours is less likely. Low doses may also result in early respiratory depression, typically within the first hour after administration^45,46. Despite respiratory depression being a dreaded complication, clinically significant episodes are rarely seen, even with high doses of 100 micrograms of fentanyl⁴⁶. Although no clinically significant instances of delayed respiratory depression have been reported following a single injection of intrathecal fentanyl, there are chances that continuous infusions or repeated doses of lipophilic opioids could potentially lead to significant delayed respiratory depression⁴⁶. The risk of development of respiratory depression increases due to certain factors. These include the administration of large doses of opioids, concurrent use of other opioids and sedatives, administration in opioid-naive patients, and elderly patients over 65 years. Detecting respiratory depression be a challenging task on account of several factors. Bradypnea may or may not be observed, and significant hypercapnia can be demonstrated even if the respiratory rate appears normal. Pulse oximetry can be useful in monitoring oxygen saturation levels⁴⁵. However, a lowered consciousness is the most reliable clinical indicator of respiratory depression. Despite varying monitoring protocols, 4 to 6 hours of monitoring is advised after intrathecal fentanyl administration^46,47.

Urinary retention:

A significant side effect of intrathecal opioids is urinary retention. A study reported a 30% occurrence of urinary retention when a low-dose continuous infusion of fentanyl five micrograms per hour was gradually administered over a 24-hour period^48,49. Urinary retention is not a common side effect of intrathecal fentanyl⁵⁰.

Nausea and vomiting:

Intrathecal fentanyl has the notable characteristic of being less emetogenic when compared to hydrophilic opioids^51,52. This can be attributed to the inhibitory effect of fentanyl on visceral pain impulses, which can trigger nausea and vomiting. Another factor is the reduction in the use of supplemental analgia in the form of parenteral opioids which are emetogenic in nature⁵³.

Hypotension:

Intrathecal opioids can potentially reduce maternal plasma catecholamine levels, resulting in hypotension. Furthermore, opioids can directly elicit a sympatholytic effect within the spinal cord⁵².

CONCLUSION:

Fentanyl stands out among synthetic opioids due to its higher potency, quicker onset of action, and rapid redistribution within the body. Its use in recent times has increased due to its ability to ultimately enhance post-operative analgesia. Despite the better efficacy of alpha-2 agonists at providing post-operative analgesia, especially dexmedetomidine, the haemodynamic changes observed, especially bradycardia and hypotension, are undesirable in certain patient groups such as the elderly, patients with comorbidities and haemodynamically unstable patients. Under these conditions, intrathecal fentanyl emerges as a superior adjuvant that can be used in conjunction with various local anaesthetic agents as well as general anaesthesia. Combined with other anaesthesia modes, intrathecal fentanyl can provide adequate analgesia while maintaining stable haemodynamic parameters. The adverse effects are minimal and usually self-limiting and reduces use of parenteral opioids. Thus, the safety profile and pharmacological features of fentanyl make it an ideal drug to be used in the field of anaesthesia.

ACKNOWLEDGMENTS:

The authors thank the Department of Anaesthesiology, Jawaharlal Nehru Medical College, Datta Meghe Institute of Higher Education and Research.

REFERENCES:

1. Kenneth C, Mohamed AN. Opioid Agonists and Antagonists. In Stoelting’s Pharmacology and Physiology in Anesthetic Practice, Edited by: Lippincott Williams and Wilkins United States of America. 5th ed.; 2015; 217–256.

2. Stanley T. H. Fentanyl. Journal of Pain and Symptom Management. May 2005; 29(5): 67–71. doi.org/10.1016/j.jpainsymman.2005.01.009

3. Cosgrave et al. Intrathecal Opioids. Pain Tutorial. (2020, January 23). WFSA Resource Library. Available on https://resources.wfsahq.org/atotw/intrathecal-opioids/

4. Andrew Hindle. Intrathecal Opioids in The Management of Acute Postoperative Pain. Continuing Education in Anaesthesia Critical Care and Pain. June 2008; 8(3): 81–5. doi.org/10.1093/bjaceaccp/mkn016

5. Grape S. et al. Management of Adverse Effects of Intrathecal Opioids in Acute Pain. Best Practice and Research: Clinical Anaesthesiology. 2023; June; 37(2): 199-207. doi: 10.1016/j.bpa.2023.02.002.

6. Koning et al. Intrathecal Hydrophilic Opioids for Abdominal Surgery: A Meta-Analysis, Meta-Regression, And Trial Sequential Analysis. British Journal of Anaesthesia. 2020; Sep; 125(3): 358–372. doi.org/10.1016/j.bja.2020.05.061

7. Abate S. M., Belihu A. E. Efficacy of Low Dose Bupivacaine with Intrathecal Fentanyl for Cesarean Section on Maternal Hemodynamic: Systemic Review and Meta-Analysis. Saudi Journal of Anaesthesia. 2019; 13(4): 340–351. doi.org/10.4103/sja.SJA_17_19

8. Bajwa et al. Comparison of Intrathecal Clonidine and Fentanyl In Hyperbaric Bupivacaine For Spinal Anesthesia And Postoperative Analgesia In Patients Undergoing Lower Abdominal Surgeries. Saudi Journal of Anaesthesia. 2017; 11(3): 589–593. doi: 10.4103/aer.AER_91_17

9. Ebrie et al. Hemodynamic and Analgesic Effect of Intrathecal Fentanyl with Bupivacaine in Patients Undergoing Elective Cesarean Section; A Prospective Cohort Study. Plos One. 2022; Jul 7; 17(7). Doi: 10.1371/journal.pone.0268318

10. Farzi et al. Comparing the Effect of Adding Fentanyl, Sufentanil, and Placebo with Intrathecal Bupivacaine on Duration of Analgesia and Complications of Spinal Anesthesia in Patients Undergoing Cesarean Section. Anesthesiology and Pain Medicine. 2017; 7(5). Doi: 10.5812/aapm.12738

11. Hussien R. M., Rabie A. H. Sequential Intrathecal Injection of Fentanyl and Hyperbaric Bupivacaine at Different Rates: Does It Make a Difference? A Randomized Controlled Trial. Korean Journal of Anesthesiology. 2019; 72(2): 150–155. doi.org/10.4097/kja.d.18.00173

12. Jouybar. et al. Comparative Efficacy of three Adjuvant Medications Used in Combination with Intrathecal Bupivacaine for Caesarian Section Anesthesia: A Randomized, Double-Blind Clinical Trial. Current Therapeutic Research, Clinical and Experimental. 2022; 97: 100688. doi: 10.1016/j.curtheres.2022.100688

13. Kalbande, et al. Addition of Dexmedetomidine and Fentanyl to Intrathecal Hyperbaric Bupivacaine for Lower Limb Surgeries: A Randomized, Comparative Study. Cureus. 2022; 14(8). Doi: 10.7759/cureus.28276

14. Kararmaz et al. Which Administration Route of Fentanyl Better Enhances the Spread Of Spinal Anaesthesia: Intravenous, Intrathecal Or Both?. Acta Anaesthesiologica Scandinavica. 2003; 47(9): 1096-100. doi: 10.1034/j.1399-6576.2003.00231.x.

15. Kumar et al. A Randomized Controlled Study Between Fentanyl and Butorphanol with Low Dose Intrathecal Bupivacaine to Facilitate Early Postoperative Ambulation in Urological Procedures. Anesthesia Essays and Researches. 2016; 10(3): 508–511. doi.org/10.4103/0259-1162.179320

16. Naaz et al. A Comparative Study of Analgesic Effect of Intrathecal Nalbuphine and Fentanyl as Adjuvant in Lower Limb Orthopaedic Surgery. Journal of clinical and diagnostic research. 2017; 11(7): UC25-UC28. doi: 10.7860/JCDR/2017/24385.10224.

17. Park et al. Comparison of Bupivacaine plus Intrathecal Fentanyl and Bupivacaine Alone for Spinal Anesthesia with Intravenous Dexmedetomidine Sedation: A Randomized, Double-Blind, Noninferiority Trial. Regional Anesthesia and Pain Medicine. 2019; Apr; 44(4): 459-465. doi.org/10.1136/rapm-2018-100084

18. Rahimzadeh et al. Comparative Addition of Dexmedetomidine and Fentanyl to Intrathecal Bupivacaine in Orthopedic Procedure in Lower Limbs. BMC Anesthesiology. 2018; 62 (2018). doi.org/10.1186/s12871-018-0531-7

19. Routray et al. Comparison of Intrathecal Clonidine and Fentanyl as Adjuvant to Hyperbaric Bupivacaine in Subarachnoid Block for Lower Limb Orthopedic Surgery. Anesthesia Essays and Researches. 2017; 11(3); 589–593. Doi: 10.4103/aer.AER_91_17

20. Sabertanha et al. The Effect of Intrathecal Bupivacaine Plus Dextrose 5% and Fentanyl Compared with Bupivacaine Alone on the Onset and Duration of Analgesia in Patients Undergoing Lower-Limb Orthopedic Surgery. Advances In Orthopedics. 2023; 2023: 2496557. doi: 10.1155/2023/2496557

21. Sawhney et al. Use of Intrathecal Midazolam or Fentanyl as an Adjunct to Spinal Anaesthesia with Bupivacaine for Lower Limb Surgery: A Randomised Controlled Study. Medical journal, Armed Forces India. 2019; 75(2): 176-183. doi: 10.1016/j.mjafi.2018.07.009.

22. Sharma et al. Comparison of Intrathecal Bupivacaine-Fentanyl and Bupivacaine-Butorphanol Combinations for Joint Replacement Surgeries. Journal Of Anaesthesiology, Clinical Pharmacology. 2022; 38(1): 79–83. Doi: 10.4103/joacp.JOACP_94_20

23. Sharma et al. Comparison of Nalbuphine Versus Fentanyl as Intrathecal Adjuvant to Bupivacaine for Orthopedic Surgeries: A Randomized Controlled Double-Blind Trial. Journal Of Anaesthesiology, Clinical Pharmacology. 2021; 37(4): 529-536. doi: 10.4103/joacp.JOACP_270_18.

24. Singh et al. Intrathecal Buprenorphine Versus Fentanyl as Adjuvant To 0.75% Ropivacaine in Lower Limb Surgeries. Journal Of Anaesthesiology, Clinical Pharmacology. 2016; 32(2): 229–233. doi: 10.4103/0970-9185.182107

25. Weigl et al. Analgesic efficacy of intrathecal fentanyl during the period of highest analgesic demand after cesarean section: A randomized controlled study. Medicine (Baltimore). 2016; 95(24): e3827. doi: 10.1097/MD.0000000000003827

26. Gautam et al. Comparison of Fentanyl and Dexmedetomidine as Intrathecal Adjuvants to Spinal Anaesthesia for Abdominal Hysterectomy. Journal of the Nepal Medical Association. 2018; 56(213): 848-855. doi: 10.31729/jnma.3739.

27. Kılıçkaya et al. Comparison of the Effects of Intrathecal Fentanyl and Intrathecal Morphine on Pain in Elective Total Knee Replacement Surgery. Pain Research and Management. December 2016; 2016: 3256583. Doi:10.1155/2016/3256583

28. Bindra et al. Postoperative Analgesia with Intrathecal Nalbuphine versus Intrathecal Fentanyl in Cesarean Section: A Double-Blind Randomized Comparative Study. Anesthesia, essays and researches. 2018; 12(2): 561-565. doi: 10.4103/aer.AER_41_18.

29. Satapathy et al. A Comparative Study of Intrathecal Fentanyl and Nalbuphine as an Adjuvant to Hyperbaric Bupivacaine for Spinal Anesthesia in Lower Limb Orthopedic Surgeries: A Prospective, Double-Blind, Randomized Controlled Study. Cureus. 2023; 15(6): e41230. doi: 10.7759/cureus.41230

30. Gupta et al A Comparative Study of Intrathecal Dexmedetomidine and Fentanyl as Adjuvants to Bupivacaine. Journal Of Anaesthesiology, Clinical Pharmacology. 2011; 27(3): 339–343. doi: 10.4103/0970-9185.83678

31. Bagle et al. To Compare the Efficacy of Intrathecal Clonidine and Intrathecal Fentanyl as An Adjuvant to Hyperbaric Bupivacaine for Infra-Umbilical Urological Surgeries. Journal of Pharmaceutical Negative Results. 2023; 7378–86. doi: 10.47750/pnr.2022.13. S09.864.

32. Duggal et al. A Comparison of Intrathecal Levobupivacaine with Hyperbaric Bupivacaine for Elective Cesarean Section: A Prospective Randomized Double-Blind Study. Journal of Obstetric Anaesthesia and Critical Care. 2015; (2): 78. Doi :10.4103/2249-4472.165135

33. Chaudhary et al. Rationalized Approach for The Treatment of Neuropathic Pain. Research Journal of Pharmacy and Technology. August 2021; 14(5): 2887-5. doi: 10.52711/0974-360X.2021.0050736.

34. Marc B. S, Tony L. Y. Pharmacology of Spinal Opioids. Journal of Pain and Symptom Management. 1990; 5(3): 191-203. doi: 10.1016/0885-3924(90)90009-9.

35. Allman K, Wilson I, O’Donnell A. Drug formulary. Oxford Handbook of Anaesthesia. Edited by Oxford University Press 198 Madison Avenue, New York, NY 10016, United States of America. 2022; 4th ed: 1172.

36. Laxminarayana K B et al. An Insight on pain modulation with Gender and Obesity: A Systematic Review. Research Journal of Pharmacy and Technology. 2020; 13(12): 6284-90. doi: 10.5958/0974-360X.2020.01093.8

37. Grape et al. Management of adverse effects of intrathecal opioids in acute pain. Best Practice and Research Clinical Anaesthesiology. 2023; 37(2): 199-207. https://doi.org/10.1016/j.bpa.2023.02.002.

38. Sudireddy Rajini, B.S. Venkateswarlu. A Study on Pain Assessment and Management in Post-Operative patients. Research Journal of Pharmacy and Technology. 2021; 14(3): 1612-1614. doi: 10.5958/0974-360X.2021.00286.9

39. Ms. L. Parimala, E. Amutha. Effectiveness of Foot Massage on Pain, Heart Rate and Blood Pressure among Abdominal Surgery Patients Research Journal of Pharmacy and Technology. 2019; 12(9): 4426-4428. doi: 10.5958/0974-360X.2019.00762.5

40. Uppal et al. Efficacy of Intrathecal Fentanyl for Cesarean Delivery: A Systematic Review and Meta-analysis of Randomized Controlled Trials with Trial Sequential Analysis. Anesthesia and Analgesia. 2020; 130(1): 111-125. doi: 10.1213/ANE.0000000000003975

41. Peng, P. W., Sandler, A. N. A Review of The Use of Fentanyl Analgesia in The Management of Acute Pain in Adults. Anesthesiology. 1999; 90(2): 576-99. doi: 10.1097/00000542-199902000-00034.

42. Morshed et al. Pattern of Analgesic Use in Post-Operative Pain Management in a Tertiary Level Teaching Hospital in Bangladesh. Research Journal of Pharmacy and Technology. 2016; 9(5): 493-496. doi: 10.5958/0974-360X.2016.00091.3

43. Morshed et al. Pattern of Analgesic Use in Post-Operative Pain Management in a Tertiary Level Teaching Hospital in Bangladesh. Research Journal of Pharmacy and Technology. 2016; 9(5): 493-496. doi: 10.5958/0974-360X.2016.00091.3

44. Ayushma et al. Study of Intrathecal Buprenorphine for Postoperative Analgesia after Cesarean section. Research Journal of Pharmacy and Technology. 2019; 12(12): 6062-6066. doi: 10.5958/0974-360X.2019.01052.7

45. Syeda et al. A Comparative Study of NSAIDs and Opioids V/S NSAIDs and TCAs Perioperatively for Pain Management in the Department of Orthopaedics. Research Journal of Pharmacy and Technology. 2022; 15(12): 5501-6. doi: 10.52711/0974-360X.2022.00928

46. Dinesh et al. Current Opioid Access, Use and Problems in Asian Jurisdictions. Research Journal of Pharmacy and Technology. 2020; 13(4): 1989-1994. doi: 10.5958/0974-360X.2020.00358.3

47. Rathmel et al. The role of intrathecal drugs in the treatment of acute pain. Anesthesia and Analgesia. 2005; 101(5 Suppl): S30-S43. doi: 10.1213/01.ANE.0000177101.99398.22

48. Chaney M. A. Side effects of intrathecal and epidural opioids. Canadian journal of anaesthesia. 1995; 42(10): 891-903. doi: 10.1007/BF03011037.

49. Szarvas et al. Neuraxial opioid-induced pruritus: a review. Journal of Clinical Anesthesia. 2003; 15(3): 234-9. doi: 10.1016/s0952-8180(02)00501-9.

50. Rallabhandi et al. Evaluation of transdermal fentanyl patch as pre-emptive analgesia for improvement of postoperative pain relief in patients undergoing major abdominal sugeries under general anaesthesia Journal of Evolution of Medical and Dental Sciences. 2020; 9(47): 3556-3559. DOI: 10.14260/jemds/2020/780

51. Fonseca et al. Safety and Effectiveness of Adding Fentanyl or Sufentanil to Spinal Anesthesia: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Brazilian Journal Of Anesthesiology. 2023; 73(2): 198-216. doi: 10.1016/j.bjane.2021.10.010.

52. Gautam et al. Comparison of Fentanyl and Dexmedetomidine as Intrathecal Adjuvants to Spinal Anaesthesia for Abdominal Hysterectomy. Journal of the Nepal Medical Association. 2018; 56(213): 848-855. doi: 10.31729/jnma.3739.

Received on 18.06.2023 Modified on 06.08.2023

Research J. Pharm. and Tech 2024; 17(6):2959-2966.

DOI: 10.52711/0974-360X.2024.00463