Opiate

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Harvesting the poppy pod. Harvesting opium.jpg
Harvesting the poppy pod.

Opiate is a term classically used in pharmacology to mean a drug derived from opium. Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors in the brain (including antagonists). [1] Opiates are alkaloid compounds naturally found in the opium poppy plant Papaver somniferum. [2] The psychoactive compounds found in the opium plant include morphine, codeine, and thebaine. Opiates have long been used for a variety of medical conditions with evidence of opiate trade and use for pain relief as early as the eighth century AD. [3] Opiates are considered drugs with moderate to high abuse potential and are listed on various "Substance-Control Schedules" under the Uniform Controlled Substances Act of the United States of America.

Contents

In 2014, between 13 and 20 million people used opiates recreationally (0.3% to 0.4% of the global population between the ages of 15 and 65). [4] According to the CDC, from this population, there has been a recorded 47,000 deaths with a total of a half a million deaths from 2000–2014. [5] In 2016, the World Health Organization reported that 27 million people suffer from opioid abuse disorder. They also reported that in 2015, 450,000 people died as a result of drug use, with between a third and a half of that number being attributed to opioids. [6]

Overview

Codeine Codein - Codeine.svg
Codeine
Chemical structure of morphine Morphin - Morphine.svg
Chemical structure of morphine

Opiates belong to the large biosynthetic group of benzylisoquinoline alkaloids, and are so named because they are naturally occurring alkaloids found in the opium poppy. The major psychoactive opiates are morphine, codeine, and thebaine. Papaverine, noscapine, and approximately 24 other alkaloids are also present in opium but have little to no effect on the human central nervous system. Alkaloids that have no effect on the central nervous system are not considered to be opiates. Very small quantities of hydrocodone and hydromorphone are detected in assays of opium on rare occasions; it appears to be produced by the plant under circumstances and by processes which are not understood at this time and may include the action of bacteria.[ citation needed ] Dihydrocodeine, oxymorphol, oxycodone, oxymorphone, metopon and possibly other derivatives of morphine and/or hydromorphone also are found in trace amounts in opium.[ citation needed ]

Despite morphine being the most medically significant opiate, larger quantities of codeine are consumed medically, most of it synthesized from morphine. Codeine has greater and more predictable oral bioavailability, making it easier to titrate the dose. Codeine also has less abuse potential than morphine, and because it is milder, larger doses of codeine are required. [7]

Morphine addiction cure advertisement in the year 1900 MorphineAdvertisement1900 - no watermark.JPG
Morphine addiction cure advertisement in the year 1900

Opiate withdrawal syndrome effects are associated with the abrupt cessation or reduction of prolonged opiate usage.

The manifestation of opiate dependence and abuse relies on a variety of factors, including the opiate's pharmacokinetic properties and the user's predisposition for addiction. [8]

Synthesis

While the full synthesis of opioids from naphthoquinone (Gates synthesis) or other simple organic starting materials is possible, they are tedious and uneconomical processes. Therefore, most of the opiate-type analgesics in use today are either extracted from Papaver somniferum or synthesized from those opiates, especially thebaine. [9]

In 2015 researches reported successful biosynthesis of thebaine and hydrocodone using genetically modified yeast. Once scaled for commercial use the process would cut production time from a year to several days and could reduce costs by 90%. [10] [11]

Pharmacokinetics

Codeine

Codeine is a prodrug which is converted to morphine and acts on μ-opiate receptors. It is converted to morphine by metabolism of CYP2D6 enzymes. Individuals who have lower CYP2D6 activity may not metabolize codeine efficiently enough to experience its analgesic effects. Conversely, individuals with higher CYP2D6 activity may metabolize the drug too quickly and experience dose-related side effects such as sedation and respiratory depression. [12] With the report of codeine-related deaths in children, codeine should no longer be prescribed due to its adverse effects and poor efficacy. [13]

Fentanyl

Fentanyl is a synthetic opioid structurally similar arylpiperidines. It is a strong μ-receptor agonist that is 80–100 times more potent to morphine, and has a fast onset with a shorter duration of action than morphine. It is metabolized in the liver by CYP3A4 enzymes to norfentanyl, an inactive drug. [14]

Heroin

Global estimates of drug users in 2016
(in millions of users) [15]
SubstanceBest
estimate
Low
estimate
High
estimate
Amphetamine-
type stimulants
34.1613.4255.24
Cannabis 192.15165.76234.06
Cocaine 18.2013.8722.85
Ecstasy 20.578.9932.34
Opiates 19.3813.8026.15
Opioids 34.2627.0144.54

Heroin, the brand name for diacetylmorphine, is the first of several semi-synthetic opioids to be derived from morphine, a component of natural opium. [16] Although it is derived from, rather than directly found in, natural opium, it is commonly referred to as an opiate.[ citation needed ] Heroin (diacetylmorphine) is a morphine prodrug; it is metabolized by the liver into morphine after administration. One of the major metabolites of heroin, 6-monoacetylmorphine (6-MAM), is also a morphine prodrug.

Hydromorphone

Hydromorphone is used as alternative to morphine. It has a high first-pass metabolism, and is primarily glucuronidated in the liver to hydromorphone-3-glucoronide (H3G). 75% of hydromorphone is renally excreted, with 7% excreted as the parent opiate. [14]

Meperidine

Meperidine is a synthetic opiate part of the arylpiperidine class. It is a strong μ-receptor agonist with 1/10th the potency of morphine. It is used to treat rigors, and has a half-life of three to four hours. It is hepatically metabolized to the active metabolites of normeperidine, normepiridinic acid, and medperidinic acid. Normeperidine at toxic levels can cause CNS excitation and seizures. [14]

Methadone

Methadone has a higher bioavailability and half life compared to morphine. [17] It is metabolized to an inactive product by N-demethylation by CYP3A4 enzymes in the liver. It has high person to person variability because of varying levels of CYP3A4 in individuals. [18] It is approved for treatment of moderate to severe pain as well as opioid dependence. [19] Because of its high risk of drug interactions, liver toxicity, and patient variability, patients have to be monitored closely at methadone clinics. [20]

Morphine

Nicomorphine (morphine dinicotinate), dipropanoylmorphine (morphine dipropionate), desomorphine (di-hydro-desoxy-morphine), methyldesorphine, acetylpropionylmorphine, dibenzoylmorphine, diacetyldihydromorphine, and several others are also derived from morphine. [21]

Morphine is metabolized in the liver to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G), and are excreted by the kidneys. They are also able to cross into the blood-brain barrier into the cerebrospinal fluid. M6G has potent analgesic activity, binds to opioid receptors, and is a main contributor to the therapeutic benefit of morphine. [22] M3G does not act as an analgesic, has a low affinity for opioid receptors, and may possibly antagonize the therapeutic effects of morphine and M6G. Moreover, high doses of morphine, and thus M3G, is associated with neurotoxic side effects such as hyperalgesia, allodynia and myoclonus. [23]

Oxymorphone

Oxymorphone is a congener of morphine. It is metabolized to 6-hydroxy-oxymorphone and oxymorphone-3-glucuronide, and 40% is excreted as metabolites. 6-hydroxy-oxymorphine is active and exists in a 1:1 ratio with the parent drug. Oxymorphone-3-glucuronide's activity is unknown. [14]

Indication

Opiates are mainly used for pain management with the premise that there will be benefits for both pain & function that will outweigh the risks to the patient. [24]

Opiate dose conversions may be necessary when switching medications given the differing pharmacodynamics between opiates. Generally, morphine is used as the standard for converting between opiates to achieve equivalent analgesic effects. These differences in morphine-equivalents may differ between formulations of the same medication. [25] Calculating total daily dose using morphine milligram equivalents is used to identify patients at risk of overdose. [26]

Complications and side effects

Common side effects associated to opioid use include: sedation, nausea, dizziness, vomiting, constipation, physical dependence, tolerance, and respiratory depression. Of these the most common are constipation & nausea and there are no development of tolerance to these side effects. [27] This is why stool softeners or laxatives (polyethylene glycol, docusate, and senna) are often prescribed with opioids. [28]

Less common side effects include: delayed gastric emptying, hyperalgesia, immunologic and hormonal dysfunction, muscle rigidity, and myoclonus. [29]

Opiate use for pain is widely accepted in the healthcare system. However, long-term treatment for chronic pain is highly controversial as there is a high risk of addiction associated with its use leading to abuse and diversion to others even when taken properly. [30] Those addicted to opiates will prioritize acquiring these drugs over other activities in their lives, negatively impacting their professional and personal relationships.

Chronic opioid use can lead to tolerance. This often causes the patient to need higher and/or more frequent doses of the drug to get the desired effects. [31]

Concentration-dependence adverse effects may vary based on the user's genetic polymorphisms which can alter drug metabolism. Cytochrome P450 (notably CYP2D6) is responsible for the metabolism of various opiates to active metabolites and variations in CYP450 activity lead to varying serum drug levels. [32]

Pharmacology in pain

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. It is an essential defensive function where pain works as an alarm to avoid or limit tissue damage. Opiates act upon opioid receptors that are coupled to inhibitor G protein coupled receptors (GPCR). These receptors fall into 3 classes: μ (mu), δ (delta), and κ (kappa) receptors. [33]

More than 70% of opioid receptors are μ receptors, predominantly located on the central terminals of nociceptors in the dorsal horn of the spinal cord. The remaining 30% of opioid receptors are located post-synaptically on dendrites of second-order spinothalamic neurons & interneurons. [33]

When an opiate binds as an agonist to the GPCR, there will be a signaling cascade resulting in the inhibition of adenylate cyclase and calcium ion channels with the stimulation of potassium ion channels. The net effect of these changes is a reduced intracellular cAMP and hyperpolarization of the neuronal cell reducing neurotransmitter release. [34] Through this pathway, when opiates bind to and activate the mu receptor, there is a decrease transmission of pain signalling. This pathway targeted for the analgesia properties that opiates are known and used for. Other clinically important roles of mu are its involvement in respiratory and cardiovascular functions, gastrointestinal peristalsis, feeding, and mood. [35] These other pathways are important because they explain the side effects of opiate use like respiratory depression at high doses, constipation with chronic use, and addicting properties. [29]

Absolute contraindications

Those with the following conditions should not be using opioids: [36]

Risk factors for prescription abuse

The following are risk factors for opiate prescription abuse: [37]

Statistically, middle-aged patients with substance use history and psychiatric comorbidities are seen with higher mortality risks such as suicide.

See also

Related Research Articles

Heroin Opioid drug primarily used recreationally

Heroin, also known as diamorphine among other names, is an opioid most commonly used as a recreational drug for its euphoric effects. It is used medically in several countries to relieve pain or in opioid replacement therapy. It is typically injected, usually into a vein, but it can also be smoked, snorted, or inhaled. The onset of effects is usually rapid and lasts for a few hours.

Hydrocodone Opioid drug used in pain relief

Hydrocodone, sold under the brand name Hysingla among others, is an opioid used to treat severe pain of a prolonged duration, if other measures are not sufficient. It is also used as a cough suppressant in adults. It is taken by mouth. Typically it is sold as the combinations acetaminophen/hydrocodone or ibuprofen/hydrocodone. By itself it is sold in a long-acting formulation.

Morphine Pain medication of the opiate family

Morphine is a pain medication of the opiate family which is found naturally in a number of plants and animals, including humans. It acts directly on the central nervous system (CNS) to decrease the feeling of pain. It can be taken for both acute pain and chronic pain. It is frequently used for pain from myocardial infarction and during labor. It can be given by mouth, by injection into a muscle, by injection under the skin, intravenously, injection into the space around the spinal cord, or rectally. Maximum effect is reached after about 20 minutes when given intravenously and after 60 minutes when given by mouth, while duration of effect is 3–7 hours. Long-acting formulations also exist.

Methadone group of stereoisomers

Methadone, sold under the brand name Dolophine among others, is an opioid used for opioid maintenance therapy in opioid dependence and for chronic pain management. Detoxification using methadone can be accomplished in less than a month, or it may be done gradually over as long as six months. While a single dose has a rapid effect, maximum effect can take up to five days of use. The pain-relieving effects last about six hours after a single dose. After long-term use, in people with normal liver function, effects last 8 to 36 hours. Methadone is usually taken by mouth and rarely by injection into a muscle or vein.

Oxycodone Opioid medication

Oxycodone, sold under the brand name OxyContin among others, is an opioid medication used for treatment of moderate to severe pain, and a common drug of abuse. It is usually taken by mouth, and is available in immediate-release and controlled-release formulations. Onset of pain relief typically begins within 15 minutes and lasts for up to six hours with the immediate-release formulation. In the United Kingdom, it is available by injection. Combination products are also available with paracetamol (acetaminophen), ibuprofen, naloxone, and aspirin.

Thebaine chemical compound

Thebaine (paramorphine), also known as codeine methyl enol ether, is an opiate alkaloid, its name coming from the Greek Θῆβαι, Thēbai (Thebes), an ancient city in Upper Egypt. A minor constituent of opium, thebaine is chemically similar to both morphine and codeine, but has stimulatory rather than depressant effects. At high doses, it causes convulsions similar to strychnine poisoning. The synthetic enantiomer (+)-thebaine does show analgesic effects apparently mediated through opioid receptors, unlike the inactive natural enantiomer (−)-thebaine. While thebaine is not used therapeutically, it is the main alkaloid extracted from Papaver bracteatum and can be converted industrially into a variety of compounds, including hydrocodone, hydromorphone, oxycodone, oxymorphone, nalbuphine, naloxone, naltrexone, buprenorphine and etorphine. Butorphanol can also be derived from thebaine.

Narcotic Chemical substance with psycho-active properties

The term narcotic originally referred medically to any psychoactive compound with sleep-inducing properties, and euphoric properties as well. In the United States, it has since become associated with opiates and opioids, commonly morphine and heroin, as well as derivatives of many of the compounds found within raw opium latex. The primary three are morphine, codeine, and thebaine.

Tramadol Medication of the opioid type

Tramadol, sold under the brand name Ultram among others, is an opioid pain medication used to treat moderate to moderately severe pain. When taken by mouth in an immediate-release formulation, the onset of pain relief usually begins within an hour. It is also available by injection. It may be sold in combination with paracetamol (acetaminophen) or as longer-acting formulations.

Hydromorphone chemical compound

Hydromorphone, also known as dihydromorphinone, and sold under the brand name Dilaudid among others, is an opioid used to treat moderate to severe pain. Typically, long-term use is only recommended for pain due to cancer. It may be used by mouth or by injection into a vein, muscle, or under the skin. Effects generally begin within half an hour and last for up to five hours.

Opioid Psychoactive chemical

Opioids are substances that, when reaching opioid receptors, have effects similar to those of morphine. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use disorder, reversing opioid overdose, suppressing cough, as well as for executions in the United States. Extremely potent opioids such as carfentanil are approved only for veterinary use. Opioids are also frequently used non-medically for their euphoric effects or to prevent withdrawal.

Oxymorphone Chemical compound

Oxymorphone, sold under the brand names Numorphan and Opana among others, is an opioid pain medication. Pain relief after injection begins after about 5–10 minutes, after oral administration it begins after about 30 minutes, and lasts about 3–4 hours for immediate-release tablets and 12 hours for extended-release tablets. The elimination half-life of oxymorphone is much faster intravenously, and as such, the drug is most commonly used orally. Like oxycodone, which metabolizes to oxymorphone, oxymorphone has a high potential to be abused.

Nalbuphine chemical compound

Nalbuphine, sold under the brand names Nubain among others, is an opioid analgesic which is used in the treatment of pain. It is given by injection into a vein, muscle, or fat.

Opioid-induced hyperalgesia (OIH) or opioid-induced abnormal pain sensitivity, also called paradoxical hyperalgesia, is a phenomenon associated with the long-term use of opioids such as morphine, oxycodone, and methadone. OIH is characterized as generalized pain that is not necessarily confined to the affected site. Over time, individuals taking opioids can develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). Some studies on animals have also demonstrated this effect occurring after only a single high dose of opioids.

Thebacon Chemical compound

Thebacon, or dihydrocodeinone enol acetate, is a semisynthetic opioid that is similar to hydrocodone and is most commonly synthesised from thebaine. Thebacon is a derivative of acetyldihydrocodeine, where only the 6–7 double bond is saturated. Thebacon is marketed as its hydrochloride salt under the trade name Acedicon, and as its bitartrate under Diacodin and other trade names. The hydrochloride salt has a free base conversion ratio of 0.846. Other salts used in research and other settings include thebacon's phosphate, hydrobromide, citrate, hydroiodide, and sulfate. The US DEA Administrative Controlled Substance Control Number assigned by the Controlled Substances Act 1970 for thebacon and all of its salts is 9737.

Diacetyldihydromorphine chemical compound

Diacetyldihydromorphine is a potent opiate derivative developed in Germany in 1929 which is rarely used in some countries for the treatment of severe pain such as that caused by terminal cancer, as another form of diamorphine. Diacetyldihydromorphine is fast-acting and longer-lasting than diamorphine, with a duration of action of around 4-7 hours.

Codeine Opiate used to treat pain

Codeine is an opiate used to treat pain, coughing, and diarrhea. It is typically used to treat mild to moderate degrees of pain. Greater benefit may occur when combined with paracetamol (acetaminophen) or a nonsteroidal anti-inflammatory drug (NSAID) such as aspirin or ibuprofen. Evidence does not support its use for acute cough suppression in children or adults. In Europe, it is not recommended as a cough medicine in those under 12 years of age. It is generally taken by mouth. It typically starts working after half an hour, with maximum effect at two hours. Its effects last for about four to six hours.

Oxymorphazone chemical compound

Oxymorphazone is an opioid analgesic drug related to oxymorphone. Oxymorphazone is a potent and long acting μ-opioid agonist which binds irreversibly to the receptor, forming a covalent bond which prevents it from detaching once bound. This gives it an unusual pharmacological profile, and while oxymorphazone is only around half the potency of oxymorphone, with higher doses the analgesic effect becomes extremely long lasting, with a duration of up to 48 hours. However, tolerance to analgesia develops rapidly with repeated doses, as chronically activated opioid receptors are rapidly internalised by β-arrestins, similar to the results of non-covalent binding by repeated doses of agonists with extremely high binding affinity such as lofentanil.

An equianalgesic chart is a conversion chart that lists equivalent doses of analgesics. Equianalgesic charts are used for calculation of an equivalent dose between different analgesics. Tables of this general type are also available for NSAIDs, benzodiazepines, depressants, stimulants, anticholinergics and others as well.

Opioid overdose Toxicity due to excessive opioids

An opioid overdose is toxicity due to excessive opioids. Examples of opioids include morphine, heroin, fentanyl, tramadol, and methadone. Symptoms include insufficient breathing, small pupils, and unconsciousness. Onset of symptoms depends in part on the route by which the opioids are taken. Among those who initially survive, complications can include rhabdomyolysis, pulmonary edema, compartment syndrome, and permanent brain damage.

Opioid withdrawal syndrome is a condition that occurs when opioid users who are physiologically dependent upon opioids abruptly reduce or stop opioid use.

References

  1. Hemmings, Hugh C.; Egan, Talmage D. (2014). Pharmacology and Physiology for Anesthesia: Foundations and Clinical Application: Expert Consult - Online and Print. Elsevier Health Scienc,es. p. 253. ISBN   978-1437716795. Opiate is the older term classically used in pharmacology to mean a drug derived from opium. Opioid, a more modern term, is used to designate all substances, both natural and synthetic, that bind to opioid receptors (including antagonists).
  2. "Opiate - Definitions from Dictionary.com". dictionary.reference.com. Retrieved 2008-07-04.
  3. Brownstein, M J (1993-06-15). "A brief history of opiates, opioid peptides, and opioid receptors". Proceedings of the National Academy of Sciences of the United States of America. 90 (12): 5391–5393. doi:10.1073/pnas.90.12.5391. ISSN   0027-8424. PMC   46725 . PMID   8390660.
  4. "Status and Trend Analysis of Illict[sic] Drug Markets" (PDF). World Drug Report 2015. Retrieved 26 June 2015.
  5. "CDC Press Releases". CDC. 2016-01-01. Retrieved 2019-10-17.
  6. "WHO | Information sheet on opioid overdose". WHO. Retrieved 2019-10-21.
  7. "Canadian Guideline for Opioid Use for Pain — Appendix B-8: Opioid Conversion and Brand Availability in Canada". nationalpaincentre.mcmaster.ca. Retrieved 2016-04-18.
  8. Gruber, Staci A.; Silveri, Marisa M.; Yurgelun-Todd, Deborah A. (2007-09-01). "Neuropsychological Consequences of Opiate Use". Neuropsychology Review. 17 (3): 299–315. doi:10.1007/s11065-007-9041-y. ISSN   1573-6660. PMID   17690984.
  9. Synthesis of morphine alkaloids Presentation School of Chemical Sciences, University of Illinois at Urbana-Champaign Archived 2013-02-28 at the Wayback Machine retrieved 12-02-2010
  10. Galanie, Stephanie; Thodey, Kate; Trenchard, Isis J.; Interrante, Maria Filsinger; Smolke, Christina D. (2015-09-04). "Complete biosynthesis of opioids in yeast". Science. 349 (6252): 1095–1100. doi:10.1126/science.aac9373. ISSN   0036-8075. PMC   4924617 . PMID   26272907.
  11. Mobley, Emily (2015-08-13). "Yeast cells genetically modified to create morphine-like painkiller". The Guardian. ISSN   0261-3077 . Retrieved 2016-04-17.
  12. Kirchheiner, J.; Schmidt, H.; Tzvetkov, M.; Keulen, J.-Tha; Lötsch, J.; Roots, I.; Brockmöller, J. (August 2007). "Pharmacokinetics of codeine and its metabolite morphine in ultra-rapid metabolizers due to CYP2D6 duplication". The Pharmacogenomics Journal. 7 (4): 257–265. doi: 10.1038/sj.tpj.6500406 . ISSN   1473-1150. PMID   16819548.
  13. Friedrichsdorf, Stefan J.; Nugent, Andrea Postier; Strobl, A. Quinn (2013). "Codeine-associated pediatric deaths despite using recommended dosing guidelines: three case reports". Journal of Opioid Management. 9 (2): 151–155. doi:10.5055/jom.2013.0156. ISSN   1551-7489. PMID   23709324.
  14. 1 2 3 4 Inturrisi, Charles E. (July 2002). "Clinical pharmacology of opioids for pain". The Clinical Journal of Pain. 18 (4 Suppl): S3–13. doi:10.1097/00002508-200207001-00002. ISSN   0749-8047. PMID   12479250.
  15. "Annual prevalence of use of drugs, by region and globally, 2016". World Drug Report 2018. United Nations Office on Drugs and Crime. 2018. Retrieved 7 July 2018.
  16. Copeland, CS (Jul–Aug 2014). "The Human Side of the Heroin Epidemic" (PDF). Healthcare Journal of New Orleans.CS1 maint: date format (link)
  17. Grissinger, Matthew (August 2011). "Keeping Patients Safe From Methadone Overdoses". Pharmacy and Therapeutics. 36 (8): 462–466. ISSN   1052-1372. PMC   3171821 . PMID   21935293.
  18. Ferrari, Anna; Coccia, Ciro Pio Rosario; Bertolini, Alfio; Sternieri, Emilio (December 2004). "Methadone--metabolism, pharmacokinetics and interactions". Pharmacological Research. 50 (6): 551–559. doi:10.1016/j.phrs.2004.05.002. ISSN   1043-6618. PMID   15501692.
  19. Anderson, Ilene B; Kearney, Thomas E (January 2000). "Use of methadone". Western Journal of Medicine. 172 (1): 43–46. doi:10.1136/ewjm.172.1.43. ISSN   0093-0415. PMC   1070723 . PMID   10695444.
  20. Lugo, Ralph A.; Satterfield, Kristin L.; Kern, Steven E. (2005). "Pharmacokinetics of methadone". Journal of Pain & Palliative Care Pharmacotherapy. 19 (4): 13–24. doi:10.1080/J354v19n04_05. ISSN   1536-0288. PMID   16431829.
  21. "Esters of Morphine". www.unodc.org. United Nations Office on Drugs and Crime. Retrieved 10 March 2012.
  22. Christrup, L. L. (January 1997). "Morphine metabolites". Acta Anaesthesiologica Scandinavica. 41 (1): 116–122. doi:10.1111/j.1399-6576.1997.tb04625.x. PMID   9061094.
  23. Andersen, Gertrud; Christrup, Lona; Sjøgren, Per (January 2003). "Relationships among morphine metabolism, pain and side effects during long-term treatment: an update". Journal of Pain and Symptom Management. 25 (1): 74–91. doi: 10.1016/s0885-3924(02)00531-6 . ISSN   0885-3924. PMID   12565191.
  24. Cohen, Brandon; Preuss, Charles V. (2019), "Opioid Analgesics", StatPearls, StatPearls Publishing, PMID   29083658 , retrieved 2019-10-31
  25. Patanwala, Asad E; Duby, Jeremiah; Waters, Dustin; Erstad, Brian L (2007-02-01). "Opioid Conversions in Acute Care". Annals of Pharmacotherapy. 41 (2): 255–267. doi:10.1345/aph.1H421. ISSN   1060-0280. PMID   17299011.
  26. "Morphine Equivalent Units/Morphine Milligram Equivalents". www.asam.org. Retrieved 2019-11-10.
  27. Benyamin, Ramsin; Trescot, Andrea M.; Datta, Sukdeb; Buenaventura, Ricardo; Adlaka, Rajive; Sehgal, Nalini; Glaser, Scott E.; Vallejo, Ricardo (2008). "Opioid complications and side effects". Pain Physician. 11 (2 Suppl): S105–120. ISSN   1533-3159. PMID   18443635.
  28. Publishing, Harvard Health. "Pain relief, opioids, and constipation". Harvard Health. Retrieved 2019-10-24.
  29. 1 2 Benyamin, Ramsin; Trescot, Andrea M.; Datta, Sukdeb; Buenaventura, Ricardo; Adlaka, Rajive; Sehgal, Nalini; Glaser, Scott E.; Vallejo, Ricardo (March 2008). "Opioid complications and side effects". Pain Physician. 11 (2 Suppl): S105–120. ISSN   1533-3159. PMID   18443635.
  30. Reference, Genetics Home. "Opioid addiction". Genetics Home Reference. Retrieved 2019-10-24.
  31. Abuse, National Institute on Drug. "Prescription Opioids". www.drugabuse.gov. Retrieved 2019-10-24.
  32. Foster, Adriana; Mobley, Elizabeth; Wang, Zixuan (2007). "Complicated Pain Management in a CYP450 2D6 Poor Metabolizer". Pain Practice. 7 (4): 352–356. doi:10.1111/j.1533-2500.2007.00153.x. ISSN   1533-2500. PMID   17986163.
  33. 1 2 Fornasari, Diego (2014). "Pain pharmacology: focus on opioids". Clinical Cases in Mineral and Bone Metabolism. 11 (3): 165–168. ISSN   1724-8914. PMC   4269136 . PMID   25568646.
  34. Pathan, Hasan; Williams, John (2012). "Basic opioid pharmacology: an update". British Journal of Pain. 6 (1): 11–16. doi:10.1177/2049463712438493. ISSN   2049-4637. PMC   4590096 . PMID   26516461.
  35. Pasternak, Gavril W.; Pan, Ying-Xian (October 2013). "Mu Opioids and Their Receptors: Evolution of a Concept". Pharmacological Reviews. 65 (4): 1257–1317. doi:10.1124/pr.112.007138. ISSN   0031-6997. PMC   3799236 . PMID   24076545.
  36. "Appendix C – Opioid Pharmacology". ICSI. Retrieved 2019-10-24.
  37. Webster, Lynn R. (2017). "Risk Factors for Opioid-Use Disorder and Overdose". Anesthesia and Analgesia. 125 (5): 1741–1748. doi:10.1213/ANE.0000000000002496. ISSN   1526-7598. PMID   29049118.