Acute Pain Management in the Opioid-Dependent Patient

image

Based on Lisa Doan, Joseph Largi, Lynn Choi, and Christopher Gharibo

INTRODUCTION

Opioid use is increasing worldwide leading to an increasing amount of opioid-tolerant patients who may require acute pain management. Pain in this patient population is often poorly understood and therefore may be inadequately treated. The main goals in treating acute pain in opioid-tolerant patients are providing effective pain relief and minimizing withdrawal symptoms. Other challenges include assisting with social issues, poor coping, and psychiatric issues. This chapter discusses important factors to consider when treating acute pain in opioid-dependent patients.

DEFINITIONS

Tolerance

Tolerance is a physiologic adaptation in which increasing amount of a drug is required to achieve the same pharmaco- logic effects after prolonged use. Tolerance develops to most effects of opioids, including analgesia, euphoria, sedation, respiratory depression, and nausea; however, tolerance does not develop to miosis or constipation.1

Withdrawal

Withdrawal refers to physiologic symptoms resulting from the abrupt discontinuation of chronically administered opioids. Although withdrawal from opioids is rarely life threatening, it can be very uncomfortable. The symptoms of opioid withdrawal include abdominal cramps, anxiety, diarrhea, disturbed sleep, irritability, dysphoria, nausea and vomiting, rhinorrhea, urinary frequency, twitching, lacrimation, and increased muscle spasms.

Clinical Pearls

  • The symptoms of opioid withdrawal include abdominal cramps, anxiety, diarrhea, disturbed sleep, irritability, dysphoria, nausea and vomiting, rhinorrhea, urinary frequency, twitching, lacrimation, and increased muscle spasms.

The onset and time course of opioid withdrawal are deter- mined by the half-life of the drug (Figure1). Withdrawal symptoms of short-acting opioids such as heroin and morphine typically begin more rapidly than long-acting agonist opioids such as methadone. Symptoms of withdrawal with short-acting opioids start 6–24 hours after the last dose, peak at 24–48 hours, and resolve within 5–10 days. Methadone is a long-acting opioid agonist; its withdrawal symptoms emerge 36–48 hours after the last dose. Some low-grade symptoms of withdrawal may linger for 3–6 weeks after last use due to its long half-life.2

Clinical Pearls

  • Withdrawal symptoms may develop in opioid-tolerant patients if their usual dose of opioids is stopped, reduced too quickly, or the effect of the opioid is reversed by an antagonist such as naloxone.
  • Withdrawal symptoms can occur even with small decreases (10%–15%) in opioid dosing and can mani- fest as myalgias and arthralgias in addition to return of the pain.



Figure-1Symptoms and duration of heroin and methadone withdrawal.

Substance Abuse and Dependence

Before the release of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders in 2013, substance abuse and dependence were considered two separate disor- ders. They are now considered to be a single disorder mea- sured on a continuum from mild to severe. Substance abuse and dependence are now recognized as the recurrent maladap- tive use of a substance that leads to clinically significant impairment or distress personally, professionally, or socially.3 Physical dependence is recognized as a state of adaption mani- fested by withdrawal symptoms that can be elicited by abrupt discontinuation, rapid dose reduction, or the administration of an antagonist.4

Addiction

Addiction is defined as the continued use of a substance despite adverse consequences. It is a behavioral syndrome characterized by evidence of psychological dependence or craving, use despite harmful adverse effects, and other drug-related aberrant behav- ior (eg, altering prescriptions, drug hoarding or sales, unsanc- tioned dose escalation).

Maintenance

Maintenance therapy aims to prevent the craving and with- drawal symptoms of opioid-dependent individuals by substitut- ing substances with long-acting and less euphoric opioids such as methadone and buprenorphine.5 The goals of treatment are to achieve a stable maintenance dose of opioid agonist and mitigate withdrawal symptoms.

TYPES OF OPIOID-TOLERANT PATIENTS

Anesthesiologists and pain medicine specialists often encounter patients who are opioid dependent. The majority of this patient population have chronic pain conditions and have been using opioid analgesics for a prolonged period of time. The chronic pain can be a result of cancer or a nonmalignant process. The use of opioids in the management of cancer pain has been widely accepted.6 The estimated cancer prevalence in the United States was over 12 million in 2009.7 It is estimated that 20%–50% of cancer patients experience pain as a presenting symptom and that up to 90% experience pain in the advanced stages of disease.8 The estimated prevalence of chronic noncan- cer pain is predicted to increase as the population ages. The use of opioids in chronic noncancer pain has become increasingly common, and guidelines have been set forth by the American Pain Society, the American Academy of Pain Medicine, and the American Society of Interventional Pain Physicians for this purpose.9,10 However, evidence for the efficacy of long-term opioid use in noncancer pain has been inconclusive. With the increasing awareness of the potential adverse consequences of long-term opioid use, a “universal precautions” approach with appropriate risk assessment and management has been recom- mended. This approach includes proper diagnosis for the etiol- ogy of pain; informed consent; the use of treatment agreements; assessment of analgesia, activity, adverse effects, and aberrant behavior; and careful documentation.11 The smaller portion of the opioid-dependent population includes opioid abusers. Heroin is the most common illicit opioid that is abused, although its use has plateaued over the past 10 years. However, prescription opioids are increasingly being abused. Prescription opioid sales quadrupled between 1999 and 2010.12 In 2010, the number of Americans reporting nonmedical use of prescription opioids reached 12 million.13 Since 2003, more deaths due to opioid overdose have involved prescription opioid analgesics than heroin and cocaine com- bined.14 Further complicating the picture is that opioid abuse and misuse may also be seen in patients prescribed opioids for chronic pain. In a review examining the prevalence of addiction in chronic pain patients, prevalence varied from 0%–31%.15 Patients with a past history of opioid abuse in methadone or buprenorphine opioid treatment programs compose another subpopulation of opioid-dependent patients who may need acute pain management.

Pain is prevalent in patients with a history of opioid abuse. In studies of patients receiving methadone maintenance treatment, 61% report chronic pain, and 37% report severe chronic pain.16,17 Increased reports of pain may occur as a result of opioid- induced hyperalgesia (OIH), which occurs when the long-term use of opioids causes a hypersensitivity to painful stimuli.18

TOLERANCE AND OPIOID-INDUCED HYPERALGESIA MECHANISMS

Tolerance can develop after the prolonged use of opioids. It is a phenomenon that is described as a decrease in the effect of a drug after repeated administration, which can be overcome by increasing the dose of the drug. OIH is a mechanism by which the analgesic properties of a drug are decreased secondary to increased pain sensitivity. As a result of OIH and tolerance, opioid-dependent patients may have a lower pain threshold and require higher doses of opioids to achieve adequate pain relief. It is important to recognize that while OIH and tolerance are distinctly different processes, they are related and have overlap- ping mechanisms. While tolerance causes a rightward shift in the dose-response curve, OIH leads to a downward shift in the dose-response curve (Figure-2).



Figure-2In opioid-naïve patients, increasing the opioid dose results in increased analgesia (1). In opioid-tolerant patients, the baseline threshold remains the same, but an increased dose of opioid is required to reach the same analgesic effect (2). Note that in opioid-
induced hyperalgesia, maximal analgesic effect is not reached, baseline pain tolerance is reduced, and there is a downward shift from the opioid-tolerant patient (3).

Clinical Pearls

  • The initial clinical strategy for the treatment of tolerance and OIH are similar: regional anesthesia techniques, optimize nonopioids, control withdrawal, and adjust opioid doses.

OIH should be suspected when the effect of opioids seems to decrease in the absence of disease progression, especially if found in the context of diffuse allodynia unrelated to the origi- nal pain or increased levels of pain with increasing opioid requirements.

19 The precise molecular mechanisms underlying tolerance and OIH are not fully understood and are still being investigated. Tolerance is classically thought to be due to the downregulation of opioid receptors. However, other mecha- nisms likely play a role, as well, such as adaptations downstream of receptor activation.20 OIH has many proposed mechanisms, including those involving the central glutaminergic system, spinal dynorphins, descending facilitation, genetic mecha- nisms, and enhanced nociceptive responses.21

The Glutaminergic System

Current data suggest that the most likely molecular mechanism of OIH involves the central glutaminergic system. The main mechanisms by which opioids trigger the glutaminergic system involve the activation of N-methyl-D-aspartate (NMDA) receptors, which are glutamate receptors; the inhibition of glu- tamate reuptake; and the activation of protein kinase C.22 Ani- mal studies have shown that the coadministration of ketamine, an NMDA receptor antagonist, with morphine reduces analge- sic tolerance as well as the development of OIH after the cessa- tion of systemic or intrathecal morphine administration.23 Similarly, human studies have found that the administration of ketamine attenuated remifentanil induced OIH as measured by intradermal electrical stimulation. Low-dose ketamine has been reported to prevent remifentanil-induced postoperative hyper- algesia in humans.24

Spinal Dynorphins

Spinal dynorphins are endogenous opioid peptides that are modulators of the pain response. It has been shown that levels of spinal dynorphin are increased with continuous infusions of opioids.
25 These increases are associated with hyperalgesia that can be reversed with dynorphin antiserum.

Descending Facilitation

Another proposed mechanism of the development of OIH is the facilitation of descending pathways from the rostral ven- tromedial medulla. The rostral ventromedial medulla has both descending inhibitory and excitatory projections to the spinal cord. The subset of excitatory neurons that facilitate nociceptive processing has been shown to be involved in OIH.
26

Enhanced Nociceptive Responses

Another proposed mechanism of OIH is a decrease in the reup- take of neurotransmitters from the primary afferent fibers and enhanced responsiveness of spinal neurons to nociceptive neu- rotransmitters, such as substance P and glutamate. Morphine administration over several days has been shown to increase substance P and the expression of its receptor, the NK-1 recep- tor, in the spinal cord.27

Genetic Contributions

Many studies have supported the conclusion that genetic influ- ences play a crucial role in pain sensitivity and analgesic response and therefore also in OIH.

ACUTE PAIN MANAGEMENT OF THE OPIOID-DEPENDENT PATIENT

Despite opioid tolerance and/or dependence, effective pain management during the perioperative period is an achievable goal by treating acute pain aggressively with nonopioid and opioid medications and by using nonpharmacological modali- ties and early mobilization.

Preoperative Assessment and Management

Clinical Pearls

  • Opioid-tolerant patients can often be identified during preoperative assessment.
  • In some patients, tolerance may not become evident until a diminished response to intraoperative opioids is noted or when postoperative pain control becomes challenging.
  • Patients with chronic pain on opioids and other cen- trally acting analgesics should be advised to continue
  • taking their medications as prescribed, including on the morning of surgery.

A crucial first step in the management of the perioperative pain in opioid-dependent patients is identifying the extent of opioid tolerance in a given patient. In some patients, the diag- nosis can be made by the preoperative assessment, whereas in others, tolerance may not become evident until a diminished response to intraoperative opioids is noted or when postop- erative pain control is found to be difficult. Some patients may be willing to divulge their opioid use or abuse history, whereas others may be reluctant due to a distrust of the medi- cal community and concern of discrimination by being labeled a drug seeker by medical staff. Therefore, it is impor- tant that the provider begin to gain the patient’s trust from the first meeting with the patient. A clue in the patient’s his- tory that may indicate possible opioid tolerance and depen- dence is the abuse of nonopioid substances. Patients who abuse other substances, such as alcohol, marijuana, or nico- tine, are more likely to have opioid dependence than the general population.28 When deception is suspected, the pro- vider can administer a urine toxicology screen, which, in addi- tion to screening for opioids, will also screen for other drugs of abuse, which can aid in the management of the patient.29 The provider should provide reassurance that acute pain man- agement is realistic and to make sure that both the patient and the medical team are working towards a common goal. The provider should also be careful to maintain privacy and confi- dentiality in an attempt to build trust. The plan for the patient should be discussed in a nonjudgmental manner. In addition to the usual preoperative assessment, certain addi- tional information should be obtained from the opioid- dependent patient. This includes the documentation of all medications and their doses. This is especially important when trying to provide adequate postoperative analgesia and to prevent withdrawal from opioids or other medications. These medications and doses should be confirmed with the original provider of the prescriptions, the patient’s pharmacy, and, when applicable, the patient’s methadone clinic.

Clinical Pearls

  • Provide reassurance that acute pain management is realistic.
  • Maintain privacy and confidentiality, and build trust.
  • Discuss the plan in a nonjudgmental manner.
  • Document all medications the patient is taking, along with the medication doses
  • Confirm medications and doses with the original provider.
  • Keep in mind the psychosocial aspect of pain; pain is often compounded by anxiety and depression.
  • Continue antidepressant and anti-anxiety medications perioperatively.
  • Avoid naltrexone and naloxone in the perioperative period.
  • Advise continuation of pain medications as prescribed, including the morning of surgery.

It is important to remember that patients who are being treated for chronic pain often exhibit poor coping and have a psychosocial aspect to their pain that is compounded by anxi- ety and depression. For this reason, antidepressants and anti- anxiety medications should be continued during the perioperative period. In patients with opioid abuse, it is also important to note that the perioperative period is not an opti- mal time to detoxify the patient. Opioid antagonists such as naltrexone and naloxone are not advised in the perioperative period for an opioid-dependent patient. The postoperative administration of these drugs can bring upon withdrawal symptoms in this patient population, which may place the patient at medical risk, especially in the presence of comor- bidities. If the administration of an opioid antagonist is needed for respiratory depression, it should be administered carefully in titrated doses.

Patients with chronic pain on opioids should be advised to continue taking their medications as prescribed, including on the morning of surgery. Strong consideration can be given to preoperative dosing with nonsteroidal anti-inflammatory drugs (NSAIDs) such as celecoxib, intravenous acetaminophen, or anticonvulsants on the morning of surgery.

Patients with a history of opioid abuse may be in opioid treatment programs using methadone or buprenorphine. It is important for providers to understand that maintenance opi- oids typically have no analgesic effect at their prescribed dos- ages, likely because of tolerance or OIH; therefore, in most cases, the maintenance dose should be continued. Methadone and buprenorphine, in addition to being used for the treatment of opioid abuse, may also be used in the treatment of pain and are discussed below.

Clinical Pearls

  • Patients on methadone maintenance should continue their verified methadone dose throughout hospitalization.
  • The treatment of acute pain can be challenging in patients treated for opioid dependence with buprenor- phine. Because of its long half-life and high affinity for the mu-opioid receptor, buprenorphine competes with other opioids attempting to bind to opioid receptors, thus preventing appropriate analgesia. Therefore, options include stopping buprenorphine or switching to another opioid before surgery.

Methadone

Methadone is a long-acting opioid agonist that also has activ- ity as an NMDA antagonist. Methadone is the most com- monly used medication to treat opioid addiction. The half-life of methadone is long and variable, ranging from 12–28 hours.
30 Methadone has a biphasic elimination curve with a rapid alpha-elimination phase followed by a much longer beta-elimination phase. Thus, for maintenance treatment of opioid addiction, the use of methadone once daily prevents withdrawal. However, the analgesic effects of methadone require more frequent dosing.31 Due to methadone’s proper- ties as an NMDA antagonist, it may reduce opioid tolerance and OIH. Methadone has certain pharmacological characteristics that require precautions with its use. Methadone is metabolized by the cytochrome P450 enzyme, primarily CYP3A4 and CYP2B6, in the liver. Because of its P450 metabolism, methadone has many drug interactions. For example, the use of P450 inducers (eg, phenytoin, rifampin), antiretrovirals (eg, efavirenz), and P450 inhibitors (eg, azole-based antifungals) will each result in a different methadone metabolism, thus affecting plasma levels and therapeutic effect. With inhibitors of methadone metabo- lism, side effects such as sedation and respiratory depression can also occur.30

Clinical Pearls

  • Patients on methadone maintenance should continue their verified methadone dose throughout hospitalization.
  • Methadone is metabolized by the cytochrome P450 enzyme.
  • Because of its P450 metabolism, methadone has many drug interactions.
  • The use of P450-inducing medications such as phenyt- oin, rifampin, and antiretrovirals (eg, efavirenz or P450 inhibitors such as azole-based antifungals) affect the plasma level and therapeutic effect of methadone.

Methadone may prolong the QT interval, which can lead to fatal cardiac arrhythmias. Caution should be used when methadone is combined with other drugs that may also pro- long the QT interval. Caution should be exercised when switching from one opioid to methadone, because the pharmacokinetics of methadone can vary greatly from person to person, potentially leading to overdose if the conversion results in greater than expected potency of methadone. Patients being switched from higher doses of opioids to methadone seem to be at greater risk for toxicity.32 Due to the variable pharmacokinetics of methadone, consultation with a pain medicine specialist should be considered when the use of methadone is contemplated.

Patients on methadone maintenance with acute pain should continue their verified methadone dose and be prescribed mul- timodal analgesia, likely including short-acting opioids to treat the incident pain.

Buprenorphine

Buprenorphine is a partial mu-opioid agonist. For the treat- ment of opioid addiction, buprenorphine comes in tablets that are taken sublingually, formulated either with buprenor- phine alone or combined with naloxone. Transdermal buprenorphine is indicated for the management of moderate to severe chronic pain. Buprenorphine has a long half-life of approximately 37 hours. Thus, for the treatment of addiction it can be used once daily. The transdermal formulation offered in the U.S. is meant to be changed every 7 days. Buprenor- phine is also metabolized by the hepatic cytochrome P450 system, primarily CYP3A4 and CYP2B6. It may also be asso- ciated with a prolongation of the QT interval.30 Buprenor- phine has great affinity for the mu-opioid receptor, approximately 1000 times that of morphine.33 For that reason, it may precipitate withdrawal in patients already on opioids because its high receptor affinity displaces other opi- oids. However, in a patient who has stopped using opioids and is in withdrawal, buprenorphine will ease symptoms of withdrawal through its partial agonist effect.30 In the U.S., buprenorphine can be prescribed at a physician’s office for opioid addiction treatment, which differs from methadone, which requires a specific methadone clinic to oversee prescrip- tion and distribution.

The treatment of acute pain can be challenging in a patient on buprenorphine with a history of opioid dependence. Because of its long half-life and high affinity for the mu-opioid receptor, buprenorphine competes with other opioids attempt- ing to bind to opioid receptors, thus interfering with analgesia. For patients on buprenorphine maintenance, there are several treatment options to consider. One option is to continue buprenorphine and add additional short-acting opioids for the acute pain. It may take larger than normal doses of short-acting opioids to provide adequate analgesia. Another option is to divide the dose of buprenorphine and administer it every 6–8 hours in an attempt to utilize its analgesic properties; additional opioids may still be required to provide adequate analgesia. A further option is to discontinue the buprenorphine altogether several days before the surgery and then restart it when the patient no longer requires opioid management for acute pain. Alternatively, buprenorphine can be converted to methadone, and short-acting opioids can be titrated for the treatment of the acute pain.34

Clinical Pearls

Treatment options for patients on buprenorphine
maintenance:
  • Continue buprenorphine maintenance, and add a short- acting opioid for acute pain.
  • Larger-than-normal doses of a short-acting opioid may be required for adequate analgesia.
  • Consider dividing buprenorphine doses q6–8 h to opti- mize its analgesic properties and adding a short-acting opioid as needed.
  • Consider discontinuing buprenorphine several days pre- operatively and restarting postoperatively.
  • Consider switching from buprenorphine to methadone perioperatively.

INTRAOPERATIVE MANAGEMENT

A multimodal approach for pain control including regional techniques and nonopioid analgesics should be considered for opioid-dependent patients. This plan ideally should be initiated preoperatively and followed throughout the perioperative period. Regional techniques and nonopioid analgesics are described in further detail in the section on postoperative care.

Clinical Pearls

  • Respiratory rate can be used as a guide for titrating opi- oids intraoperatively.
  • Opioid tolerant patients may be at an increased risk of awareness.

Patients who are opioid dependent should continue their baseline opioid dose during the perioperative period prior to the induction of anesthesia with additional analgesics provided as needed. Baseline opioids include sustained-release opioids, methadone maintenance, buprenorphine maintenance, trans- dermal fentanyl patches, and epidural or intrathecal opioid infusions. If a fentanyl patch is removed prior to surgery, a fentanyl infusion can be used during surgery as a substitute to provide maintenance opioid therapy. Patients who abuse illicit opioids such as heroin can be given either intravenous or oral doses of methadone and morphine as their baseline.35 However, determination of a baseline dose can be difficult for illicit drugs, as their formulations are variable.

Opioid-dependent patients may require larger intraoperative opioid doses than opioid-naïve patients. Respiratory rate can be used as a method to appropriately dose opioids intraoperatively. If the patient is spontaneously breathing either throughout the case or at the end after reversal of muscle relaxant, the opioid dose may be titrated to a respiratory rate of 8–12 breaths per minute. Opioid effects can also occur in the opioid-tolerant patient, including nausea, vomiting, pruritus, and respiratory depression. Therefore, it is essential to monitor vital signs and sedation level in the perioperative period while opioids are being administered even in this group of patients. If remifentanil is being used for intraoperative analgesia, a long-acting opioid at the end of the surgery can be administered to ensure analgesia after the remifentanil infusion is discontinued.

Caution is warranted if a warming blanket is used with a patient who has been administered a transdermal fentanyl or buprenorphine patch, as the application of heat over the patch may lead to an increase in medication release.

Anesthesiologists should be aware that opioid-tolerant patients under anesthesia are at an increased risk of awareness intraoperatively.
36

THE POSTOPERATIVE PERIOD

A multimodal analgesic plan should be continued into the postoperative period for opioid-dependent patients.

Opioids

Clinical Pearls

  • PCA is an effective option for postoperative analgesia. Carefully consider the basal rate dosing to decrease the probability of opioid-related side effects and complications.
  • Not all patients will need their preoperative opioid dose postoperatively. The pain generators may be different postoperatively, and the patient may require a decreased or increased dose of opioids.
  • Opioid rotation may be useful in improving efficacy, decreasing daily opioid requirements, and reducing opioid-related side effects.

A patient’s usual baseline dose of opioid is typically continued perioperatively. Intravenous patient-controlled analgesia (PCA) is an effective option for postsurgical analgesia espe- cially in the opioid-dependent patient. PCA allows the patient to administer pain medication almost instantly on an as- needed basis, decreasing the risk of under-medication and breakthrough pain and increasing patient satisfaction. By allowing patients to administer their own pain medication, demands on nursing staff are also reduced. Though not recom- mended for opioid-naïve patients, a basal rate of opioid may be administered to opioid-dependent patients to supply base- line requirements in patients not able to take oral medications.

The provider should be prepared to prescribe higher bolus doses in opioid-dependent patients compared to opioid-naïve patients and should shorten the lock-out interval for opioid- dependent patients using a PCA. Once a patient can tolerate oral medications after surgery and the pain is well controlled with PCA, the patient may be switched to oral opioids. An equianalgesic table for conversion to oral opioids is featured in Table-1. Generally, the calcu- lated equianalgesic amount of opioid medication is reduced by 50%–75% to account for incomplete cross-tolerance. Opioid rotation or switching between different opioids is an option to improve analgesia while decreasing the overall daily opioid dose and opioid-related side effects for indi- vidual compound failures despite titration. Proposed mecha- nisms for the efficacy of opioid rotation include incomplete opioid cross-tolerance, active metabolites, and different opioid and nonopioid receptor affinity.8

When rotating opioids, the equianalgesic dose should be reduced to account for incomplete cross-tolerance.

Clinical Pearls

  • Regional anesthesia should be considered for opioid- dependent patients when appropriate.

Neuraxial Anesthesia

Neuraxial anesthesia with local anesthetics and opioids can provide effective pain control while minimizing the need to administer systemic analgesics. However, neuraxially adminis- tered opioids may not effectively prevent withdrawal if systemic opioids are not given as baseline. This is due to the fact that plasma concentrations and supraspinal binding of the opioid will decrease, resulting in withdrawal symptoms.5

Regional Anesthesia

Regional anesthesia should be considered for opioid-dependent patients where appropriate, especially for surgery on the extremities. Local anesthetic infiltration, specific nerve blocks, or plexus blocks all can provide complete or adjunct analgesia.

The goal of regional anesthesia in the opioid-dependent patient is to provide adequate analgesia while also lowering or poten-

Clinical Pearls

  • Nonopioid adjuvants, including acetaminophen, NSAIDs, anticonvulsants, antidepressants, and ketamine, should be considered as part of a multimodal approach to pain control.

Ketamine

Ketamine, an NMDA receptor antagonist, can be used peri- operatively as an infusion for adjunct analgesia. A ketamine infusion has been found to reduce pain intensity and opioid consumption at 48 hours postoperatively as well as at 6 months postoperatively following spinal surgery in opioid-dependent patients.

37 A low-dose ketamine infusion used intraopera- tively and postoperatively may also enhance the effects of opi- oids, reduce opioid tolerance, and reduce opioid-induced hyperalgesia.

38,39

TABLE 1. Opioid dose equivalence table.

Drug

mg PO

mg IV

Half-life (h)

Duration (h)

Morphine

30

10

2–3

3–4

MS Contin

30

8–12

8–12

Oxycodone

20

2–3

3–4

Oxycontin

20

2–3

8–12

Hydrocodone

30

3–4

4

Hydromorphone

7.5

1.5

2–3

2–4

Alveolar ventilationMethadone

• 2

1

12–100

4–12

• 24 h oral morphine/methodone ratio


< 30 mg 2:1

• 31–99 mg 4:1

• 100–299 mg 8:1

• 300–499 mg 12:1

• 500–999 mg 15:1

• 31–99 mg 4:1

• 1000–1200 mg 20:1

• > 1200 mg, consider consult

Fentanyl

• 100 μg single dose IM/IV

10-20 min

• 80 μg buccal

• 24 h oral morphine dose/patch

48–72 per patch

• 30–59 mg = 12.5 μg/h

• 60–134 mg = 25 μg/h

• 135–224 mg = 50 μg/h

• 225–314 mg = 75 μg/h

• 315–404 mg = 100 μg/h

Oxymorphone

10

1

3–14

4–24

Tapentadol

100

4

4-6

Tramadol

200

55-7

6-8

Buprenorphine

0.4 (sublingual only)

0.3

20–70

IM, intramuscular; IV, intravenous; PO, per os (oral).

Source: Reproduced with permission from Atchabahian A, Gupta R: The Anesthesia Guide. New York: McGraw-Hill; 2013.

Acetaminophen

A single dose of intravenous acetaminophen has been found to provide 4–6 hours of effective analgesia for patients in variety of postoperative pain models with a decrease in overall opioid consumption and an increase in patient satisfaction.40 In a review of the use of intravenous acetaminophen perioperatively, the majority of studies examined showed improved analgesia and decreased opioid requirements.41 Dosing is usually 1 g intrave- nously every 6–8 hours, not to exceed the daily maximum dose of 4 g in an average-size adult patient. An oral combination opioid containing acetaminophen can be given 4 hours after intravenous acetaminophen. Care should be taken when using opioid–acetaminophen combination products to not exceed the maximum recommended daily dose of 4 g due to the risk of hepatotoxicity.

NSAIDs and Cyclooxygenase-2 Inhibitors

NSAIDs should be considered for all patients with mild or moderate acute pain unless contraindicated.42 Examples of NSAIDs include ketorolac, ibuprofen, naproxen, and the newer cyclooxygenase-2 inhibitors (COXIBs). NSAIDs provide analgesia by inhibiting prostaglandin synthesis, which results in an anti-inflammatory effect. The prostaglandin synthesis inhi- bition results in NSAID side effects, however, including gastri- tis and platelet and renal dysfunction. Because of these side effects, NSAIDs are contraindicated in patients with renal dysfunction, gastritis, and peptic ulcer disease. The COXIBs do not affect platelets and have fewer effects on the gastrointestinal system.

Ketorolac is an intravenous NSAID approved for use in the United States for the indication of acute pain. A dose of 30 mg of intravenous ketorolac is equipotent to approximately 6–10 mg of intravenous morphine. Ketorolac has been shown to have an opioid-sparing effect, and its use has resulted in reduced opioid-related side effects.43 The maximum recommended duration of use of intravenous ketorolac is 5 days.

Tramado

Tramadol is a synthetic analog of codeine that is a weak mu- opioid receptor agonist. In addition to its effect on opioid receptors, tramadol has an additional analgesic effect by inhib- iting the reuptake of norepinephrine and serotonin. Though not particularly effective in the treatment of severe pain alone, it can be used to treat mild to moderate pain in the postopera- tive period and has a lower abuse potential than other opioids.

Gabapentinoids

The gabapentinoids gabapentin and pregabalin are another option for the multimodal treatment of acute pain when they are administered in the perioperative period. The gabapenti- noids are anticonvulsants that bind to voltage-gated calcium channels, reducing the release of excitatory neurotransmitters and producing an analgesic effect. In a systematic review of the literature, a single preoperative dose of gabapentin 1200 mg improved postoperative analgesia and decreased postoperative opioid consumption. The efficacy of multiple doses of gaba- pentin perioperatively was less conclusive due to a limited number of trials.44 Based on a meta-analysis, pregabalin for postoperative pain appears to decrease opioid consumption and lower the incidence of opioid-related adverse effects postopera- tively; most studies used preoperative dosing.45 Side effects of both gabapentin and pregabalin include dizziness, ataxia, and somnolence. Table–2 presents suggested dosing regimens for these agents

A Multidisciplinary Approach

The multimodal analgesic plan should be communicated with the patient and other members of the care team. Patients with chronic pain may have anxiety or depression that may benefitfrom the input of psychology or psychiatry services.

Consulta-tion with addiction specialists should be considered in patientswith substance abuse.

TABLE 2. Dosing of perioperative gabapentin and pregabalin.

Drug

Dosing Recommendations

Gabapentin

Single preoperative dose of 1200 mg by mouth.44

Pregabalin

300 mg or 600 mg by mouth 1 hour prior to or after surgery. Consider repeating dose 12 hours after first dose.45

DISCHARGE PLANNING

The multimodal plan should be continued with suggestions for dose reductions as the acute pain episode resolves. In patients with a history of opioid abuse, consideration should be given to limiting the amount of opioid prescribed and providing for early and frequent follow-up. Referrals to pain medicine spe- cialists or addiction specialists may be considered.

REFERENCES

image

1 Gustin HB, Alik H: Opioid analgesics. In Hardman JG, Limbird LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics. New York: McGraw-Hill, 2001, pp 569–619.

2 Farrell M: Opiate withdrawal. Addiction 1994;89:1471–1475.

3 American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Publishing, 2013.

4 Stein C, Kopf A: Anesthesia and treatment of chronic pain. In Miller RD, Eriksson LI, Fleisher LA, Wiener-Kronish JP, Young WL (eds): Miller’s Anesthesia, 7th ed. Philadelphia: Churchill Livingstone, 2009, pp 1803–1804.

5 Mitra S, Sinatra RS: Perioperative management of acute pain in the opioid-dependent patient. Anesthesiology 2004;101:212–227.

6 Miaskowski C, Cleary J, Buryney R, et al; The American Pain Society: Guideline for the management of cancer pain in adults and children. Glenview, IL: American Pain Society, 2005.

7 Centers for Disease Control and Prevention. United States Cancer Statistics. http://apps.nccd.cdc.gov/uscs/. Accessed June 10, 2013.

8 Huxtable CA, Roberts LJ, Somogyi AA, et al: Acute pain management in opioid-tolerant patients: a growing challenge. Anaesth Intensive Care 2011;39:804–823.

9 Chou R, Fanciullo GJ, Fine PG, et al: Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 2009;10: 113–130.

10 Manchikanti L, Salahadin A, Atluri S, et al: American Society of Interventional Pain Physicians (ASIPP) guidelines for responsible opioid prescribing in chronic non-cancer pain: part 2—guidance. Pain Physician 2012;15:S67–S116.

11 Gourlay DL, Heit HA, Almahrezi A: Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med 2005;6:107–112.

12 Substance Abuse and Mental Health Services Administration. Results from the 2010 National Survey on Drug Use and Health: detailed table,
table 7.1.a. http://www.samhsa.gov/data/NSDUH/2k10NSDUH/tabs/ Sect7peTabs1to45.htm#Tab7.1A. Accessed June 11, 2013.

13 Centers for Disease Control and Prevention. Prescription painkiller overdose in the U.S. http://www.cdc.gov/features/vitalsigns painkilleroverdoses/. Accessed June 1, 2013.

14 Centers for Disease Control and Prevention. Vital signs: overdoses of prescription opioid pain relievers. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm6043a4.htm. Accessed June 30, 2013.

15 Minozzi S, Amato L, Davoli M, et al: Development of dependence following treatment with opioid analgesics for pain relief: a systematic review. Addiction 108:688–698, 2013.

16 Jamison RN, Kauffman J, Katz NP: Characteristics of methadone maintenance patients with chronic pain. J Pain Symptom Manage 2000; 19:53–62.

17 Rosenblum A, Joseph H, Fong C, et al: Prevalence and characteristics of chronic pain among chemically dependent patients in methadone
maintenance and residential treatment facilities. JAMA 2003;289: 2370–2378.

18 Compton P, Athanasos P, Elashoff D: Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study.J Pain 2003;4:511–19.

19 Angst MS, Clark JD: Opioid-induced hyperalgesia: a qualitative systematic review. Anesthesiology 2006;104:570–587.

20 Bailey CP, Connor M: Opioids: cellular mechanisms of tolerance and physical dependence. Curr Opin Pharmacol 2005;5:60–68.

21 Lee M, Silverman SM, Hansen H, et al: A comprehensive review of opioid-induced hyperalgesia. Pain Physician 2011;14:145–165.

22 Silverman S: Opioid-induced hyperalgesia: clinical implications for the pain practitioner. Pain Physician 2009;12:679–684.

23 Li X, Angst MS, Clark JD: A murine model of opioid-induced hyperalgesia. Brain Res Mol Brain Res 2001;86:56–62.

24 Joly V, Richebe P, Guignard B, et al: Remifentanil-induced postoperative hyperalgesia and its prevention with small-dose ketamine. Anesthesiology 2005;103:147–155.

25 Gardell LR, Wang R, Burgess SE, et al: Sustained morphine exposure induces a spinal dynorphin-dependent enhancement of excitatory transmitter release from primary afferent fibers. J Neurosci 2002;22:6747–6755.

26 Vanderah TW, Suenaga NM, Ossipov MH, et al: Tonic descending facilitation from the rostral ventromedial medulla mediates opioid- induced abnormal pain and antinociceptive tolerance. J Neurosci 2001; 121:279–286.

27 King T, Gardell LR, Wang R, et al: Role of NK-1 neurotransmission in opioid-induced hyperalgesia. Pain 2005;116:276–288.

28 O’Brien CP: Drug addiction and drug abuse. In Hardman JG, Limbrid LE (eds): Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 10th ed. New York: McGraw-Hill, 2001, pp 621–642.

29 Moeller K, Lee K, Kissack J: Urine drug screening: practical guide for clinicians. Mayo Clin Proc 2008;83:66–76.

30 Bart G: Maintenance medication for opiate addiction: the foundation of recovery. J Addict Dis 2012;31:207–225.

31 Ferrari A, Coccia CP,Bertolini A, et al: Methadone—metabolism, pharmacokinetics and interactions. Pharmacol Res 2004;50:551–559.

32 Trafton JA, Ramani A: Methadone: a new old drug with promises and pitfalls. Curr Pain Headache Rep 2009;13:24–30.

33 Bryson EO, Lipson A, Gevirtz C: Anesthesia for patients on buprenorphine. Anesthesiol Clin 2010;28:611–617.

34 Alford DP, Compton P, Samet JH: Acute pain management for patients receiving maintenance methadone or buprenorphine therapy. Ann Intern Med 2006;144:127–134.

35 Rubenstein RB, Spira I, Wolff WI: Management of surgical problems in patients on methadone maintenance. Am J Surgery 1976;131:566–569.

36 Myles PS, Leslie K, McNeil J, et al: Bispectral index monitoring to prevent awareness during anaesthesia: the B-Aware randomized controlled trial. Lancet 2004;363:1757–1763.

37 Loftus RW, Yeager MP, Clark JA, et al: Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology 2010;113:639–646.

38Suzuki M, Tseuda K, Lansing PS, et al: Small-dose ketamine enhances morphine-induced analgesia for the management of pain in an opioid addict. Anesthesiology 2002;96:1265–1266.

39 Himmelseher S, Durieux ME: Ketamine for perioperative pain management. Anesthesiology 2005;102:211–220.

40 Tzortzopoulou A, McNicol ED, Cepeda MS, et al: Single dose intravenous propacetamol or intravenous parecetamol for postoperative pain. Cochrane Database Syst Rev 2011;10:CD007126. DOI: 10.1002/14651858. CD007126.pub2.

41 Macario A, Royal MA: A literature review of randomized clinical trials of intravenous acetaminophen (paracetamol) for acute postoperative pain. Pain Pract 2011;11:290–296.

42 American Society of Anesthesiologists Task Force on Acute Pain Management: Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology 2012;116:248–273.

43 Cepeda MS, Carr DB, Miranda N, et al: Comparison of morphine, ketorolac, and their combination for postoperative pain: results from a large, randomized, double-blind trial. Anesthesiology 2005;103:1225–1232.

44 Ho KY, Gan TJ, Habib AS: Gabapentin and postoperative pain: a systematic review of randomized controlled trials. Pain 2006;126:91–101.

45 Zhang J, Ho KY, Wang Y: Efficacy of pregabalin in acute postoperative pain: a meta-analysis. Br J Anaesth 2011;106:454–462.