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Review Article

What Orthopaedic Surgeons Need to Know: The Basic Science Behind Opioids

Hagedorn, John C. II MD; Danilevich, Maxim MD; Gary, Joshua L. MD

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Journal of the American Academy of Orthopaedic Surgeons: September 15, 2019 - Volume 27 - Issue 18 - p e831-e837
doi: 10.5435/JAAOS-D-18-00438
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Although recently declared a public health crisis, the opioid epidemic has been causing pain and anguish in the United States for many years.1,2 Federal funding and assistance programs are currently being created to target some of the hardest hit populations with addition recovery resources and to encourage proper disposal of opioid medications, monitor usage of opioid prescriptions, identify those populations at risk, and educate patients.3-5 Multifaceted approaches have allowed states such as Oregon to see a 20% reduction in opioid misuse and abuse, and a 30% reduction in opioid overdose fatalities.6 Many subspecialties, such as emergency medicine, general surgery, and orthopaedic surgery, have already begun to analyze prescribing practices and provide recommendations even at the intern level.7-9 The importance of orthopaedic surgeon involvement in the opioid epidemic cannot be understated. As a community, orthopaedic surgeons prescribed the third-highest number of opioid prescriptions, and the impact on the field has been dramatic.10,11 To be responsible prescribers and lead other medical specialties through this public health crisis, it is imperative that orthopaedic surgeons know the basic science behind opioid medications.12 This review provides the orthopaedic surgeon with the mechanism of action, oral morphine equivalents (OMEs), and common issues/interactions of opioid and opioid-alternative medications (ie, acetaminophen) so that orthopaedic surgeons can be informed prescribers of these medications, while minimizing patient pain and preventing illegal diversion of these medications.

Opioids and Opioid Mechanisms of Action

The human body has four natural opioid receptors: mu (μ) (MOR), kappa (κ) (KOR), delta (δ) (DOR), and opioid receptor like-1, which are stimulated by endogenous opioids (enkephalins, endorphins, and dynorphins) to produce various responses, including analgesia13 (Table 1). These receptors are also involved in the dopamine pathway, which produces responses such as euphoria and pleasure.13,14 The MOR and DOR are thought to control analgesia, respiratory depression, euphoria, and physical dependence. The KOR receptor is primary located in the spine and produces spinal analgesia, sedation, and mild respiratory depression. Nonendogenous opioids can be broken into three classes: natural, semisynthetic, or totally synthetic (Tables 1 and 2). Natural opioids, called opiates, are derived from the poppy plant and the parent compound is opium, from which morphine, codeine, and thebaine can be extracted.15,16 Semisynthetic opioids are synthesized using chemical methods, with a natural opiate as a substrate.17 For instance, heroin and hydromorphone are made from morphine, hydrocodone from codeine, and oxycodone from thebaine.17,18 Finally synthetic opioids or opioid alternatives, such as fentanyl and tramadol, respectively, are completely synthesized in a laboratory without a natural opioid substrate.19 The goal of semisynthetic and synthetic opioids is to alter the chemical structure to have morphine-like analgesia with the potential for higher potency but with decreased adverse effects (ie, constipation, pruritis).18 Regardless of the class, nonendogenous opioids serve as selective agonists of the MOR, and in the case of tramadol, it serves as a selective agonist of the MOR and the inhibitors of serotonin and norepinephrine reuptake to achieve analgesia.20

Table 1
Table 1:
Endogenous Opioids and Opiates
Table 2
Table 2:
Semisynthetic and Total Synthetic Opioids

Several opioid receptor antagonists exist as well. These medications attach to but do not activate the opioid receptors, causing no stimulation and thus no effect. These medications can decrease the effects of endogenous and pharmacological opioids. Naloxone is an antagonist at the MOR, KOR, and DOR and is used to reverse opioid overdose. By outcompeting opioids for the receptor, the effects of the opioid are reversed, causing effects such as loss of euphoria, worsening pain, decreased nausea, decreased pruritis, and restoration of respiratory drive. Naloxone is rapidly metabolized in the liver and typically must be administered intravenously, intramuscularly, or through a nasal spray to get by first-pass liver metabolism of oral administration. It has a half-life of 60 minutes. Naltrexone is a pure MOR antagonist that can be administered orally. Typically, it is used for drug and alcohol addiction treatment by blocking the MOR and preventing the euphoria associated with opioids.21

A category of opioid partial agonists also exists. These medications activate the opioid receptors to a lesser degree than morphine and outcompete morphine, causing a decrease in the overall opioid stimulus leading to a lower peak effect. Buprenorphine is considered a partial agonist.

Mixed agonist-antagonists cause an agonist effect at the KOR and DOR but are antagonists at the MOR, thus causing pain relief without respiratory depression. Medications such as pentazocine, butorphanol, nalorphine, dezocine, and nalbuphine are mixed agonist-antagonists.21

It should be noted that not all opioids or opioid alternatives are metabolically active when given and rely on active metabolites to produce analgesia or even adverse effects.20 Morphine is a natural opioid and serves as the basis for which many other opioids are judged.22,23 It is metabolically active when administered and will produce analgesia. However, morphine does undergo metabolism by glucuronidation via UGT2B7 in the liver and kidneys, forming two clinically relevant metabolites: morphine-3-G glucuronide (M3G) and morphine-6-G glucuronide (M6G).20 The M3G metabolite is responsible for the neurotoxicity of morphine that causes seizures in humans, and the M6G metabolite is responsible for toxicity in patients who cannot adequately clear morphine from the body.20 Morphine can be detected in the body by the use of a urine drug screen (UDS)16,20 (Table 3).

Table 3
Table 3:
Narcotics Identified on UDS

Codeine is another natural opioid, but unlike morphine, it is not metabolically active when administered. Codeine becomes clinically active by being metabolized to morphine in the liver by the CYP2D6 enzyme.20 The CYP2D6 enzyme can be absent in 7% of the Caucasian population, meaning that codeine will not provide analgesia.24 Furthermore, patients who have no or low levels of active CYP2D6 can experience adverse effects, such as constipation and gastrointestinal upset, with minimal to no analgesic effect.20,25 Codeine can be identified on an UDS as either codeine or as its active metabolite, morphine16,20 (Table 3).

Hydrocodone is a semisynthetic opioid which, like codeine, is not metabolically active upon administration.20 Hydrocodone is metabolized by CYP2D6 in the liver to hydromorphone, which is metabolically active.20,25 Concern about the ability of hydrocodone to produce analgesia similarly to codeine exists in patients who have low or no CYP2D6 enzyme.25 Hydrocodone can be detected on UDS by its active metabolite, hydromorphone16 (Table 3).

Oxycodone is a semisynthetic opioid that is metabolized into two metabolically active metabolites.20 In the liver, CYP3A4 and CYP2D6 metabolize oxycodone into noroxycodone and oxymorphone, respectively.20 Although similar concerns exist regarding the CYP2D6 enzyme as with codeine and hydrocodone, the CYP3A4 is used by many common medications such as fluoxetine, atorvastatin, and erythromycin; therefore, there is concern that oxycodone can become more or less potent with these medications, as well as affect the potency of these medications.20,25 Oxycodone can be identified on an UDS by its active metabolite, oxymorphone16 (Table 3).

Hydromorphone is a semisynthetic opioid, and like morphine, it is metabolically active when administered.20 It has neuroexcitatory metabolites (hydromorphone-3-glucuronide), which can cause neurologic concerns equal to or greater than M3G during long-term treatment. For this reason, it is often given in short-acting formulations.20,26,27 Hydromorphone can be detected on an UDS16 (Table 3).

Fentanyl is a completely synthetic opioid, which is active upon administration.20 Fentanyl does undergo metabolism in the liver by CYP3A4 and can have similar interactions with medications as oxycodone.20 It is a good opioid to use in long-term treatment plans because it does not have any metabolites in common with other opiates or opioids.16,20 Due to the lack of metabolites identifiable in the urine, special UDS have to be used to detect fentanyl16 (Table 3).

Tramadol is a completely synthetic opioid alternative and, like codeine, requires metabolism to an active metabolite.20,28,29 Tramadol is metabolized in the liver by CYP2D6 and CYP3A4, where the active metabolite O-desmethyltramadol (M1) is produced.20 M1 acts as an agonist both on the MOR and on an inhibitor of serotonin and norepinephrine reuptake to achieve analgesia.20 It is this dual action of tramadol's active metabolite that makes it considered an opioid-alternative medication.20,28,29 Tramadol cannot be detected on conventional UDS and, in fact, tramadol has been shown to have a high false-positive rate for several other medications on UDS30 (Table 3).

Due to the amount of information regarding the type and characteristics of opioid and tramadol, and opioid antagonists/partial agonists, summary tables have been provided for quick reference (Tables 4 and 5).

Table 4
Table 4:
Types and Characteristics of Opioids and Tramadol
Table 5
Table 5:
Types and Characteristics of Opioid Antagonists/Partial Agonists

Nonopioid Medications and Mechanisms of Action

Several other nonopioid alternative medications exist that are crucial to understand. NSAIDs block the formation of thromboxane and prostaglandins by blocking the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzyme, respectively. NSAIDs not only decrease inflammation and pain but also decrease platelet aggregation, increasing bleeding time.31 NSAIDs are nonaddictive but do have a wide adverse-effect profile, including gastrointestinal bleeding, and have been implicated in an increased risk for myocardial infarction, stroke, and thrombotic events. NSAIDs should also be sparingly used in patients with renal dysfunction due to effects on the kidney, including acute renal failure. They should not be used in pregnant women due to fetal risk of renal complications.32 Examples of NSAIDs include acetylsalicylic acid, ibuprofen, naproxen, meloxicam, ketorolac, indomethacin, and diclofenac among multiple others.

Selective COX-2 inhibitors, as the name implies, target only COX-2 and can be beneficial in patients with gastrointestinal problems or clotting disorders but have been associated with an increased risk of thrombosis, stroke, and heart attack. Celecoxib is the only Federal Drug Administration–approved COX-2 inhibitor.33

Gabapentinoids, namely, gabapentin and pregabalin, are analogs of the neurotransmitter GABA. They do not affect the GABA receptor but have been found to affect a voltage-gated calcium channel that reduces neurotransmitter release and decreased postsynaptic excitability. This, in effect, leads to decreased epileptic activity and neuropathic pain control. It is commonly used for diabetic neuropathy and has been controversially shown to decrease pain in the acute postoperative setting.34,35

Acetaminophen (parecetamol) is a widely used medication for treating pain and fever. It is thought to act on COX-2 in the central nervous system with little peripheral anti-inflammatory effects, and more recently, it has been found to affect the endogenous cannabinoid and vanilloid system through metabolite AM404, causing a decrease in pain and temperature. Acetaminophen is hepatotoxic and total daily intake should be monitored to prevent liver disease.36

A summary table has been provided for quick reference about the type and characteristics of opioid alternative medications (Table 6).

Table 6
Table 6:
Types and Characteristics of Opioid Alternative Medications

Oral Morphine Equivalents

OMEs are a tool that can help physicians understand the strengths of various opioids and can be used to transition patients from different types of opioids with varying potencies and ensuring that their narcotic need continues to be met even when starting a different medication23,37,38 (Table 7). This can be especially helpful when transitioning patients with chronic pain between opioid medications or those in the hospital from intravenous opioid therapy to oral opioid therapy. Another instance when using OME can be useful is in the de-escalation of opioid therapy. With the reclassification of hydrocodone to a schedule II narcotic and the limitation this places on prescribing practices, many physicians must de-escalate opioid therapy faster or stop prescribing hydrocodone altogether.39,40 However, it can be easier than expected to prescribe the same number of OMEs, even when going from hydrocodone to tramadol. For instance, a prescription of hydrocodone prescribed in 5-mg pills at 30 total pills would have 150 OME; similarly, a tramadol prescription of 50-mg pills at 30 total pills still would have 150 OME. Therefore, using OME calculations can be instrumental when weaning patients from one narcotic to another to ensure that the narcotic load is decreasing.38 It should be noted again that depending on a patient's genetics, medications, and other factors, certain narcotic medications may have stronger or weaker intended effects. OME should not be used solely when judging how to transition between opioids, but it serves as an excellent guide.20

Table 7
Table 7:
OMEs for Common Narcotics

Nonopioid Medications Impact on Opioid Potency

As demonstrated by Smith, the majority of opioids are metabolized in the liver by either the CYP2D6 or CYP3A4 enzyme systems. Because many common medications, and even foods, are metabolized using the same enzyme system, the medication, the opioid, or both can experience alterations to their potency and medical effects.20Tables 8 and 9 list some common medications that can induce or inhibit the CYP3A4 and CYP2D6 enzyme systems and potentially cause difficulty with pain control, overdose, or other medical complications if not monitored closely.

Table 8
Table 8:
Examples of Select Inhibitors and Inducers of the Cytochrome P450 3A4 (CYP3A4)
Table 9
Table 9:
Examples of Select Inhibitors and Inducers of the Cytochrome P450 2D6 (CYP2D6)


Opioid abuse is a public health crisis. Government funding and treatment programs have great potential to help end this epidemic; however, multifaceted programs and the impact that the prescribing physician has on this epidemic should not be forgotten. Safe prescribing practices involve limiting opioids when possible, using nonopioids for analgesia, and knowing the basic science behind them. Opioids are a large family and can be endogenous, natural, semisynthetic, or completely synthetic. Despite the vast size of the family, all opioids, including opioid alternatives such as tramadol, provide analgesia through agonist of the MOR. Antagonists of MOR exist, such as naloxone, and serve an important role in preventing death from opioid overdose. Some opioid medications, such as morphine, are metabolically active when administered, whereas others, such as codeine, are not active until metabolized. Opioids like codeine will not be effective in the 7% of Caucasians who lack the CYP2D6 enzyme, in which case other analgesic medications should be considered. NSAIDs, selective COX-2 inhibitors, acetaminophen, and gabapentinoids are non-addictive and can add value to a multimodal pain regimen. However, certain medications, such as NSAIDs, have a wide adverse-effect profile that must be monitored.

When treating pain, it may be necessary to go between opioid medications, and use of the OME table can be helpful in controlling pain while making the transition. Using OME can also help de-escalate opioid therapy. However, OME should not be the only criteria used to judge how much pain medication to give when switching patients.

Finally, due to the role of the CYP2D6 and CYP3A4 enzyme systems in the metabolism of narcotics, physicians must be cognizant of the many common medications and foods that can induce or inhibit these enzymes to optimize opioid therapy while keeping previous medical therapies in the therapeutic range.

The opioid epidemic is here, and as orthopaedic surgeons knowing the basic science behind opioids can help lead not only orthopaedic surgeon but also the field of medicine through this devastating problem.


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Copyright 2019 by the American Academy of Orthopaedic Surgeons.