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Fentanyl - A Potent Opioid Analgesic: A Review
Journal of Developing Drugs

Journal of Developing Drugs
Open Access

ISSN: 2329-6631

+44 7868 792050

Review Article - (2016) Volume 5, Issue 3

Fentanyl - A Potent Opioid Analgesic: A Review

Ashok Kumar Sharma*, Maniratna Nareda, Sanaa Aziz, Deepak Sharma and Dr. Shiv Kumar Garg
Maharishi Arvind College of Pharmacy, Ambabari, Jaipur, Rajasthan, India, E-mail: maniratna.n@gmail.com
*Corresponding Author: Ashok Kumar Sharma, Research Scholar, Maharishi Arvind College of PharmacyMaharishi Arvind College of Pharmacy, Ambabari, Jaipur, Rajasthan, India, Tel: +91-9887593534 Email:

Abstract

Fentanyl is a potent analgesic that is almost a hundred times accented than morphine, the use of fentanyl is pain allayer and anesthetic was adopted in the medical primed. Fentanyl was first introduced by Dr. Jansen in 1959. Many type of fentanyl derivatives have been developed by adding respective substituents to the canonic molecule inorder to alter the potency, some of the ensunting molecules may exist as isomers. (The isomers of 3-methylfentanyl), which have different types of analgesic potencies depends on which is used. Bever reported that the 3rd position of a methyl group (-CH3) into the piperidine ring, increases analgesic potency. The Trans isomer was slightly more active agent than fentanyl, but its respective cis form was eight folds more active. They found that activity of the cis (+) 3-methylfentanyl more potent than fentanyl, whereas the cis negative form was less potent.

Introduction

Fentanyl is a potent analgesic that is almost a hundred times accented than morphine, the use of fentanyl is pain allayer and anesthetic was adopted in the medical primed. Fentanyl was first introduced by Dr. Jansen in 1959 [1-4].

Many type of fentanyl derivatives have been developed by adding respective substituents to the canonic molecule inorder to alter the potency, some of the ensunting molecules may exist as isomers. (The isomers of 3-methylfentanyl), which have different types of analgesic potencies depends on which is used [5-8].

Bever reported that the 3rd position of a methyl group (-CH3) into the piperidine ring, increases analgesic potency.

The Trans isomer was slightly more active agent than fentanyl, but its respective cis form was eight folds more active. They found that activity of the cis (+) 3-methylfentanyl more potent than fentanyl, whereas the cis negative form was less potent [9-15].

Chemistry

Fentanyl is a synthetic opioid related phenyl piperidine opioid agonist with the analgesic and anesthetic properties. Fentanyl acts on the mu-receptor in the central nervous system. Fentanyl stimulates the exchanges of GTP for GDP on the G-protein complex inhibits adenylate cyclase, results in a decrease in intracellular cAMP and leads the reduction in release of neurotransmitters substance like GABA, dopamine, acetylcholine and noradrenaline. The analgesic activity of fentanyl is due to the its metabolite morphine, show stimulation the opening of G-PC (G-protein coupled receptor inwardly regenerated potassium channels and blocks the opening of N-type voltage gated calcium channels resulting in hyperpolarization and reduced neuronal votability.

Fentanyl is a piperidine derivative opioid analgesic. The systematic IUPAC name is N-(1-(2-phenethyl)-4-piperidinyl-N-phenylpropanamide.

Fentanyl having its two forms as follows.

Fentanyl citrate

developing-drugs

Molecular formula: C22H28N2O.C6H8O7

Molecular weight: 528.59 gm/mol

Melting point: 154-156°C

Solubility: Fentanyl is the white colour crystalline powder soluble in water.

Fentanyl HCl

developing-drugs

Molecular formula: C22H28N2O.HCl

Molecular weight: 372.93 gm/mol

Melting point: 232°C

Solubility: White in colour

Crystalline in nature, partially soluble in water.

Analogues: The fentanyl which is the most potent analgesic in the field of medical and healthcare, which leads to the development of different type of formulation fentanyl analogues. Several fentanyl analogues used as recreational drugs by the drug abusers including β- hydroxy-3-methylfentanyl 3-Methylfentanyl, Acetyl-α-methylfentanyl, α-methylfentanyl, β-hydroxyfentanyl, thiofentanyl, α– methylthiofentanyl 3-Methylthiofentanyl.

Physical characteristic which can be used for the identification of fentanyl and its salts is that appears as white crystalline powder, due its water-soluble action fentanyl citrate is mostly used for the oral buccal dosage form (buccal lozenges) and transdermal patches, transmucosal [14-16].

Pharmacodynamics/Mechanism of Action

Fentanyl is the potent opioid analgesic. Fentanyl interacts with the opioid mu-receptor and binds with kappa (κ) and delta-type opioid receptors also. These mu-binding sites are broadly distributed in the human spinal cord, brain, and other tissues. In clinical Fentanyl show its principal pharmacologic action on the central nervous system. Its therapeutic action values are analgesia and sedation. Fentanyl depresses the respiratory centers, depresses the cough reflex, and constricts the pupils as binding the mu (μ) receptor [17-22].

Fentanyl is a pure opioid agonist, acts as interacting with opioid mureceptors located in the brain, spinal cord and smooth muscles. The primary site of therapeutic action is the central nervous system (CNS). Clinically use of fentanyl pharmacologic consequence of the interaction of fentanyl with mu-receptors is analgesic and sedative [23-26].

Opioids increase the muscle tone action and decrease the contraction of the smooth muscle in the GI tract. This the results of prolongation of GI transit time and responsible for the constipating effect of opioids. The opioids increase biliary tract pressure and some patients with biliary colic may undergo declension of pain.

Opiate receptors coupled with G-protein receptors and act as both positive and negative regulators for synaptic transmission G-proteins that activate effective proteins. Receptor binding of the opiate stimulates exchange of GTP to GDP on the G-protein complex. As system is adenylate cyclase and cAMP situated at the endo surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Opioids also show the inhibitory action the release of vasopressin, somatostatin, glucagon and insulin. The most analgesic activity of the fentanyl is due to its conversion to morphine [27-30].

Pharmacokinetics

The pharmacokinetics as absorption of fentanyl drug from the oral transmucosal drug delivery is a combination of an initial rapid absorption from buccal mucosa and more prolonged absorption of the swallowed fentanyl from the GI tract. Both the blood profile and the bioavailability of fentanyl will depend the fraction of the dose that absorbed through the oral mucosa and the fraction swallowed. The onset of action as IV (Intra venous) administration is rapid, the analgesia peak occurs within several minutes and the duration of analgesia action is 30-60 minutes after a single dose up to 100 μg [31-36].

Generally, ¼ part (25%) of the total dose of fentanyl is rapidly absorbed in the bucal mucosa and show the systemically availability. The left over ¾ parts (75%) of the total drug dose is swallowed in the saliva and slowly absorbed from the GI tract. About 25% of this amount (¼ of the total dose) escapes hepatic and intestinal first-pass elimination and able for systemically availability. Thus, generally observed 50% bioavailability of the oral transmucosal fentanyl citrateis divided between rapid transmucosal and slower GI tract absorption [37,38].

Less than 7-8% of the drug dose is excreted unchanged by the urine and only around 1% is excreted unchanged by the feces. The metabolites mainly excreted in the urine. The total plasma clearance for fentanyl was observed 0.5 Ltr/hr/kg (range 0.3 to 0.7 Ltr/hr/kg) [38-41].

Route of elimination

Fentanyl metabolized in human cytochrome P450 3A4 in isoenzyme system and eliminated by urinary system, after intravenously rout of Fentanyl approximately 75% (3/4 part) of drug is excreted by the urinary system within 72 hours [42-44].

Medicinal uses

Analgesia: The analgesic activity of fentanyl depends on the blood plasma drug level. These are the indicates for the relief of mild to severe pain [45,46].

Acute pain: Opioids are the most effective agents for the treatment of acute and severe pain for short term relief and it also controls to severe acute pain treatment. They have also been found to be important in treatment of rheumatoid arthritis and Cancer pain [47,48].

Central nervous system: Fentanyl depresses the cough reflex by the suppressing cough center in the medulla. Antitussive effects occur with the doses lower than the dose required for analgesia.

Gastrointestinal system: Fentanyl causes reduction in motility increase in muscle tone in the antrum of the stomach and duodenum. Digestion for foods is delayed in the small intestine and the propulsive contractions are decreased. Propulsive peristaltic waves in the colon are decreased the tone may increase to the point of spasm results in constipation.

Respiratory system: All the mu-receptor agonists show respiratory depression.

Intranasal: The intranasal bioavailability of fentanyl is about 80-90% but there is imprecision due to clotted pharyngeal swallow nostrils, and incorrect administration [49-52].

Side effects

Fentanyl having the following side effects [50-54].

More common:

• Blurred vision

• Chest pain

• Sore throat

• Loss of appetite

• Decreased urine

• Lightheadedness

• Rapid breathing

• Convulsions

• Increased thirst

• Lower back or side pain

• Difficult or labored breathing

• Nausea or vomiting

• Confusion

• Dry mouth

• Irregular heartbeat

Less common:

• Change in walking and balance

• Slow or fast heartbeat

• Rhythmic movement of the muscles

• Pounding in the ears

• Stomach pain

• Unsteadiness

• Decreased frequency of urination

• Shakiness in the legs, arms, hands, or feet

• Thinking abnormalities

Side Effects: Post Treatment

• Restlessness

• Weakness

• Stomach cramps

• Speech disorder

• Fentanyl Interactions

Fentanyl may interact with:

• Fentanyl shows the interaction with the mono amino oxidase inhibitors. Like isocarboxazid (Marplan) and phenelzine [55,56].

• Antagonist activity against pentazocine and butorphanol.

• Partial agonist analgesics, such as buprenorphine.

Show the interaction with the anticholinergics agents.

Fentanyl and alcohol

Use of the fentanyl with alcohol may cause of low blood pressure, sedation, respiratory depression, coma, and death.

Fentanyl and grapefruit

Potentially respiratory depression may occur if the consumption of grape fruit juice. Respiratory depression also occurs if fentanyl using with cytochrome inhibitors.

Fentanyl dosage

Fentanyl comes in five strengths which deliver fentanyl as different rates like-12 micrograms per hour (mcg/h), 25 mcg/hour, 50 mcg/ hour, 75 mcg/hour, and 100 mcg/hour.

Fentanyl overdose

Fentanyl having the following symptoms on its overdose [57].

• Difficulties breathing

• Coma

• Extreme sleepiness

• Difficulty thinking, talking, or walking

• Contraction of pupils

• Dizziness and Faintness

• Confusion

References

  1. Butch JG (2010) Clinically Oriented Pharmacology. 2nd edn. Quick Review of Pharmacology,p: 172.
  2. Lennernas B, Hedner T, Holmberg M, Bredenberg S, Nystrom C, et al. (2005) Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain. Br J Clin Pharmaco 59:249-253.
  3. Gahart BL, Nazareno AR (2015) Guideline for administration of fentanyl for pain relief in labour RCP, California.
  4. Hess R, Stiebler G, Herz A (1972) Pharmacokinetics of fentanyl in man and the rabbit. Eur J Clin Pharmacol 4: 137-141.
  5. Ernst M,Korting S, Monika N (2001) Drug reactions.8 edn. Stuttgart: Knowledge Nomic Verlagsgesell Economy. Germany, p: 286.
  6. Stanley TH (1992) The history and development of the fentanyl series. J Pain Symptom Manage 7: S3-S7.
  7. Denton JS, Donoghue ER, McReynolds J, Kalelkar M (2008) An epidemic of illicit fentanyl deaths in Cook County Illinois: September 2005 through April 2007. Journal of Forensic Sciences 53: 452-454.
  8. Drug Enforcement Administration (2007)Control of a chemical precursor used in the illicit manufacture of fentanyl as a List I chemical. Interim rule with request for comments, Federal Register 72: 20039-20047.
  9. Van Bever WF, Niemegeers CJ, Janssen PA (1947) Synthetic analgesic and pharmacology of the diastereo isomers of N-3 methyl-1-2phenyllepthy-4-piperidyl-N- phenyl propanamide. J Med Chem 17: 1047.
  10. Henderson G (1991) Fentanyl-related deaths: demographics, circumstances and toxicology in 112 cases. Journal of Forensic Sciences 36: 422-433.
  11. Higashikawa Y, Suzuki S (2008) Studies on 1-(2-phenethyl)-4-(N-propionylanilino) piperidine (fentanyl) and its related compounds. VI. Structure-analgesic activity relationship for fentanyl, methyl-substituted fentanyls and other Analogues. Forensic Toxicology 26: 1-5.
  12. Hull MJ, Juhascik M, Mazur F, Flomenbaum MA, Behonick GS (2007) Fatalities associated with fentanyl and co-administered cocaine or opiates. Journal of Forensic Sciences 52: 1383-1388.
  13. International Narcotics Control Board (2006) Psychotropic Substances: Statistics for 2004-Assessments of Annual Medical and Scientific Requirements for Substances in Schedules II, III and IV. United Nations Publications, New York, USA.
  14. Mayes S, Ferrone M (2006) Fentanyl HCl Patient-Controlled Iontophoretic Transdermal System for Pain: Pharmacology The Annals of Pharmacotherapy 40: 2178-2186.
  15. Product Information: Actiq® (1998) Oral transmucosal fentanyl citrate.Abbott Laboratories, North Chicago, IL, USA.
  16. Dhawan BN, Cesselin F, Raghubir R, Reisine T, Bradley PB, et al. (1996) International Union of Pharmacology. XII. Classification of opioid receptors 48: 567-592.
  17. Janecka A, Fichna J, Janecki T (2004) Opioid receptors and their ligands. Curr Top Med Chem 4: 1-17.
  18. Waldhoer M, Bartlett SE, Whistler JL (2004) Opioid receptors. Annu Rev Biochem73: 953-990.
  19. Brauser D (2015)Prescription Opioid Abuse Waning. Medscape Medical News.
  20. Rudd RA, Aleshire N, Zibbell JE, Gladden RM (2016) Increases in Drug and Opioid Overdose Deaths-United States, 2000-2014. MMWR Morb Mortal Wkly Rep 64: 1323-1327.
  21. Joranson DE, Gilson AM (2006) Wanted: a public health approach to prescription opioid abuse and diversion. Pharmacoepidemiol Drug Saf 15: 632-634.
  22. Compton WM, Volkow ND (2006) Major increases in opioid analgesic abuse in the United States: concerns and strategies. Drug Alcohol Depend 81: 103-107.
  23. van Dorp EL, Romberg R, Sarton E, Bovill JG, Dahan A (2006) Morphine-6-glucuronide: morphine's successor for postoperative pain relief? Anesthesia and Analgesia 102: 1789-1797.
  24. Jenkins AJ (2008) Pharmacokinetics of specific drugs. In: Karch SB (ed.), Pharmacokinetics and pharmacodynamics of abused drugs. CRC Press: Boca Raton.
  25. Morphine Sulfate(2011) The American Society of Health-System Pharmacists.
  26. Meine TJ, Roe MT, Chen AY, Patel MR, Washam JB, et al. (2005) Association of intravenous morphine use and outcomes in acute coronary syndromes: results from the CRUSADE Quality Improvement Initiative. Am Heart J 149: 1043-1049.
  27. Caraco Y, Sheller J, Wood AJ (1996) Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 278: 1165-1174.
  28. Zhang W, Chang YZ, Kan QC (2010) CYP3A4*1G genetic polymorphism influences CYP3A activity and response to fentanyl in Chinese gynecologic patients. Eur J Clin Pharmacol 66: 61-66.
  29. Zhang W, Yuan JJ, Kan QC (2011) Influence of CYP3A5*3 polymorphism and interaction between CYP3A5*3 and CYP3A4*1G polymorphisms on post-operative fentanyl analgesia in Chinese patients undergoing gynaecological surgery. Eur J Anaesthesiol 28: 245-250.
  30. Dong ZL, Li H, Chen QX (2011) Effect of CYP3A4*1G on the fentanyl consumption for intravenous patient-controlled analgesia after total abdominal hysterectomy in Chinese Han population. J Clin Pharm Ther 37: 153-156.
  31. Stamer UM, Lehnen K, Hothker F (2003) Impact of CYP2D6 genotype on postoperative tramadol analgesia. Pain 105: 231-238.
  32. Enggaard TP, Poulsen L, Arendt-Nielsen L, Brosen K, Ossig J, et al. (2006) The analgesic effect of tramadol after intravenous injection in healthy volunteers in relation to CYP2D6. Anesth Analg 102: 146-150.
  33. Poulsen L, Arendt-Nielsen L, Brosen K, Sindrup SH (1996) The hypoalgesic effect of tramadol in relation to CYP2D6. Clin Pharmacol Ther 60: 636-644.
  34. Noehr-Jensen L, Zwisler ST, Larsen F, Sindrup SH, Damkier P, et al. (2009) Escitalopram is a weak inhibitor of the CYP2D6- catalyzed O-demethylation of (+)-tramadol but does not reduce the hypoalgesic effect in experimental pain. Clin Pharmacol Ther. 86: 626-633.
  35. Ultram (2009) Prescribing Information. Division of Ortho, McNeilJanssen Pharmaceuticals Inc.,Raritan, NJ, USA.
  36. Lugo RA, Satterfield KL, Kern SE (2005) Pharmacokinetics of methadone. J Pain Palliat Care Pharmacother 19: 13-24.
  37. Fredheim OM, Moksnes K, Borchgrevink PC, Kaasa S, Dale O (2008) Clinical pharmacology of methadone for pain. Acta Anaesthesiol Scand 52: 879-889.
  38. Kharasch ED, Hoffer C, Whittington D, Sheffels P (2004) Role of hepatic and intestinal cytochrome P450 3A and 2B6 in the metabolism, disposition, and miotic effects of methadone. Clin Pharmacol Ther 76: 250-269.
  39. Ferrari A, Coccia CP, Bertolini A, Sternieri E (2004) Methadone-metabolism, pharmacokinetics and interactions. Pharmacol Res. 50: 551-559.
  40. Jasek W (2007) Austria-Codex (in German). 62nd edn. Vienna: Osterreichischer Apothekerverlag, p: 2621.
  41. Karlsen AP, Pedersen DM, Trautner S, Dahl JB, Hansen MS (2014) Safety of intranasal fentanyl in the out-of-hospital setting: A prospective observational study. Annals of Emergency Medicine 63: 699-703.
  42. Murphy A, O'Sullivan R, Wakai A, Grant TS, Barrett MJ, et al. (2014) Intranasal fentanyl for the management of acute pain in children. The Cochrane database of systematic reviews,pp: 1-32.
  43. Jasek W (2007) Austria-Codex (in German). 62nd edn. Vienna: Osterreichischer Apothekerverlag, pp: 89-92.
  44. O'Connor AB (2008) Is actiq use in noncancer-related pain really "a recipe for success?’'. Pain Medicine 9: 258-260.
  45. Shachtman N (2009) Airborne EMTs Shave Seconds to Save Lives in Afghanistan. Danger Room Wired.
  46. Smydo J (1979) Delayed respiratory depression with fentanyl. Anesth Prog 26: 47-48.
  47. Van Leeuwen L, Deen L, Helmers JH (1981) A comparison of alfentanil and fentanyl in short operations with special reference to their duration of action and postoperative respiratory depression. Anaesthesist 30: 397-399.
  48. Brown DL (1985) Postoperative analgesia following thoracotomy. Danger of delayed respiratory depression. Chest 88: 779-780.
  49. Bulow HH, Linnemann M, Berg H, Lang-Jensen T, La Cour S, et al. (1995) Respiratory changes during treatment of postoperative pain with high dose transdermal fentanyl. Acta Anaesthesiol Scand 39: 835.
  50. Nilsson C, Rosberg B (1982) Recurrence of respiratory depression following neurolept analgesia. Acta Anaesthesiol Scand 26: 240-241.
  51. McLoughlin R, McQuillan R (1997) Transdermal fentanyl and respiratory depression. Palliat Med 11: 419.
Citation: Sharma AK, Nareda M, Aziz S, Sharma D, Garg S (2016) Fentanyl - A Potent Opioid Analgesic: A Review. J Dev Drugs 5:162.

Copyright: © 2016 Sharma AK, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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