A maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by three (or more) of the following, occurring at any time in the 12-month period:
1. Tolerance, as defined by either of the following:
(a) A need for markedly increased amounts of the substance to achieve intoxication or desired effect
(b) Markedly diminished effect with continued use of the same amount of the substance
2. Withdrawal, as manifested by either of the following:
(a) The characteristic withdrawal syndrome for the substance (refer to criteria A and B of the criteria sets for withdrawal from the specific substances)
(b) The same (or a closely related) substance is taken to avoid or relieve withdrawal symptoms
3. The substance is often taken in larger amounts or for a longer period than was intended
4. There is a persistent desire or unsuccessful efforts to cut down or control substance abuse
5. A great deal of time is spent in activities to obtain the substance, use the substance, or recover from its effects
6. Important social, occupational, or recreational activities are given up or reduced because of substance use
7. The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problems that is likely to have been caused or exacerbated by the substance
With physiologic dependence: evidence of tolerance or withdrawal (i.e., either item 1 or item 2 is present)
Without physiologic dependence: no evidence of tolerance or withdrawal (i.e., neither item 1 nor item 2 is present)
Criteria for opioid withdrawal
(A) Either of the following:
1. Cessation of (or reduction in) opioid use that has been heavy and prolonged (several weeks or longer)
2. Administration of an opioid antagonist after a period of opioid use
(B) Three (or more) of the following, developing within minutes to several days after criterion A:
1. Dysphoric mood
2. Nausea or vomiting
3. Muscle aches
4. Lacrimation or rhinorrhea
5. Pupillary dilation, piloerection, or sweating
6. Diarrhea
7. Yawning
8. Fever
9. Insomnia
Table 12.2
Commonly used terms in substance dependence
Addiction | Commonly used term meaning the aberrant use of a specific psychoactive substance in a manner characterized by loss of control, compulsive use, preoccupation, and continued use despite harm; pejorative term, replaced in the “DSM-IV” in a nonpejorative way by the term substance use disorder (SUD) with psychological and physical dependence |
Dependence | 1 Psychological dependence: need for a specific psychoactive substance either for its positive effects or to avoid negative psychological or physical effects associated with its withdrawal |
2. Physical dependence: a physiologic state of adaptation to a specific psychoactive substance characterized by the emergence of a withdrawal syndrome during abstinence, which may be relieved in total or in part by re-administration of the substance | |
3. One category of psychoactive substance use disorder | |
Chemical dependence | A generic term relating to psychological and/or physical dependence on one or more psychoactive substances |
Substance use disorders | Term of DSM-IV comprising two main groups: |
1. Substance dependence disorder and substance abuse disorder | |
2. Substance-induced disorders (e.g., intoxication, withdrawal, delirium, psychotic disorders) | |
Tolerance | A state in which an increased dosage of psychoactive substance is needed to produce a desired effect; cross-tolerance: induced by repeated administration of one psychoactive substance that is manifested toward another substance to which the individual has not been recently exposed |
Withdrawal syndrome | The onset of a predictable constellation of signs and symptoms after the abrupt discontinuation of or a rapid decrease in dosage of a psychoactive substance |
Polydrug dependence | Concomitant use of two or more psychoactive substances in quantities and frequencies that cause individually significant physiologic, psychological, and/or sociological distress or impairment (polysubstance abuser) |
Recovery | A process of overcoming both physical and psychological dependence on a psychoactive substance with a commitment to sobriety |
Abstinence | Non-use of any psychoactive substance |
Maintenance | Prevention of craving behavior and withdrawal symptoms of opioids by long-acting opioids (e.g., methadone, buprenorphine) |
Substance abuse | Use of a psychoactive substance in a manner outside of sociocultural conventions |
Psychological dependence is described as a psychological need for specific substance to obtain positive effects or to avoid negative consequences. Addiction refers to the aberrant use of substance, including loss of control, compulsive use, preoccupation, and continued use despite harm. Opioid abuse or addiction is more common with polydrug abuse, or dependence on other substances, such as alcohol, marijuana, or nicotine. It is important, if possible, to distinguish the chronic pain patient from the opioid-abusing patient (Table 12.3) [6]. Unfortunately, to cloud the issue, there is significant opioid addiction within the chronic pain population, approximating 3–19 % [29]. This prevalence may be underestimated because these patients have a background of emotional and psychological instability, and develop a conditioning behavior resulting from relief of increasing pain intensity experienced from opioid use [30, 31].
Table 12.3
Distinguishing the chronic pain patient from the opioid-abusing patient
Chronic pain patient | Opioid-abusing patient |
|---|---|
Using opioids as prescribed, follows treatment plan | Out of control with opioid use, does not follow treatment plan |
Use of opioid improves quality of life | Opioids impair quality of life |
Aware and concerned about side effects | Unconcerned about side effects |
Will save previous medications, prescriptions | “Loses” prescriptions, runs out of medication early, makes excuses |
There is another group of patients who have well-documented chronic pain and resemble opioid abusers because of their often obsessive drug-seeking behavior. These patients may have visited many physicians but are under-medicated, seeking adequate pain relief. This phenomenon was termed pseudoaddiction [32]. However, unlike patients with true addiction, the pseudoaddicted patient will obtain pain relief if the dose of opioid is increased and the behavior will be eliminated.
Physiologic dependence is described as an alteration in physiologic response to a drug resulting from opioid binding to receptors, leading to withdrawal syndrome if drug is stopped. This can be seen both in patients in whom opioids are legitimately prescribed and in those abusing opioids. In general, the higher the daily dose is, the greater the degree of physiologic dependence and tolerance [33–35].
The opioid withdrawal syndrome is described as increased sympathetic and parasympathetic responses mediated via the myenteric plexus, brainstem vagal, and hypothalamic nuclei. These responses include hypertension, tachycardia, diaphoresis, abdominal cramping, and diarrhea. Quitting “cold turkey” is related to the abrupt withdrawal of opioids causing piloerection of the skin. Behavioral responses such as shaking, yawning, and leg jerking occur as well [33, 36, 37]. Rarely life threatening, these symptoms are extremely unpleasant and may be missed in the perioperative period [37]. The time course of withdrawal varies depending on the opioid being used; however, that for intermediate acting agents (e.g., morphine, heroine), it is listed in Table 12.4 [33, 38]. Abrupt halt of short-acting agents such as fentanyl or meperidine may result in withdrawal as early as 2–6 h after stopping the drug and have symptoms lasting only 4–5 days. In contrast, withdrawal from long-acting agents like methadone occurs 24–48 h after use and may last up to 6–7 weeks.
Table 12.4
Typical withdrawal symptoms associated of opioid withdrawal, by stage
Stage 1 (1–36 h) |
Anxiety |
Craving for drug |
Lacrimation |
Rhinorrhea |
Yawning |
Stage II (12–72 h) |
Diaphoresis |
Piloerection |
Anorexia |
Mydriasis |
Irritability |
Mild-moderate sleep disturbance |
Tremor |
Stage III (24–72 h) |
Abdominal pain |
Muscle spasms |
Nausea, vomiting, diarrhea |
Severe insomnia |
Violent yawning |
Opioid tolerance is a pharmacologic adaptation occurring when patients require increasing amounts of drug for same effect, shifting the dose-response curve to the right. Tolerance develops to the analgesic, euphoric, sedative, respiratory depression, and nauseating effects but not to miosis and constipation [33, 36, 37]. Duration of exposure, daily dose requirement, and receptor association/disassociation kinetics are predictive of the degree of opioid tolerance. Opioid agonists binding to the same receptor show asymmetric cross-tolerance depending on their intrinsic efficacy [33]. The number of receptors that need to be occupied to create an analgesic effect is inversely proportional to the intrinsic efficacy. In other words, a potent agonist with high efficacy binds to a small number of receptors to achieve analgesia (e.g., sufentanil). The patient treated with this agent will develop tolerance more slowly than a patient treated with opioids having low intrinsic efficacy binding to a large number of receptors (e.g., morphine) [34, 39–42]. Briefly, acquired opioid tolerance can be classified into pharmacokinetic tolerance, learned tolerance, and pharmacodynamic tolerance. The pharmacokinetic tolerance refers to enzyme induction and subsequent acceleration of opioid metabolism [43, 44]. Learned tolerance refers to decreased drug affect due to learned compensatory mechanisms (i.e., can walk a straight line while intoxicated) [45, 46]. Pharmacodynamic tolerance refers to neuroadaptive changes that take place after long-term exposure to the drug [6]. The molecular mechanisms of these adaptations are complex and result in long-term persistent neural adaptations, involving increased levels of cAMP, spinal dynorphin, glutamine, and activation of NMDA receptors [47–50]. These changes ultimately result in receptor desensitization, decreased receptor density, and alterations in receptor coupling to G proteins and signal transduction pathways [33, 46, 48, 51, 67].
Vignette #1
An example of a particularly difficult patient is the patient with history of opioid addiction presenting for an elective ventral abdominal hernia repair. In this example, the patient is taking an antidepressant for depression, oxyContin for chronic abdominal pain, and gabapentin for neuropathic symptoms. The preoperative appointment should be utilized to discuss clarify expectations and create a management strategy for post operative pain.
Issues relative to undergoing the procedure include the necessity to continue her current medications and then plan for treatment of acute surgical pain from tissue trauma. A prudent approach for this patient should start with preoperative assessment and discussion with the surgeon, anesthesiologist, psychiatrist, and social work to clarify expectations. Placement of an epidural, if feasible, would be useful in perioperative pain control. In addition to general anesthesia, adjuncts may include intravenous infusions of dexmedetomidine or other alpha 2 agonist to reduce sympathetic outflow and an NMDA antagonist. In the acute postoperative period, adequate dosing of the epidural would provide analgesia with breakthrough intravenous opioids, perhaps via patient-controlled analgesia (PCA). This may avoid acute withdrawal and treat breakthrough pain. As early as possible, the home dose of opioids should be reinstated with adequate short-acting breakthrough pain medication to cover surgical pain. This is one possible regimen to obtain pain control and subsequent early discharge.
Types and Mechanisms of Pain
Although chronic back pain is by far the most common cause of chronic pain, peripheral neuropathy, cancer, abdominal disorders, or musculoskeletal disorders such as rheumatoid arthritis and fibromyalgia are common. Many patients are afflicted with multiple disorders, which can cause different types of pain, e.g., somatic and/or neuropathic, and may benefit from targeted non-opioid modalities or a multimodal approach.
Pain begins with the stimulation of specialized nerve endings called nociceptors, which exist throughout the body on sensory nerves. Nociceptive pain accounts for both visceral (related to internal organs) and somatic (related to bones, joints, muscles) pains involved with surgery. Nociceptors respond to direct stimulation as well as to mediators such as prostaglandins, bradykinins, histamine, and serotonin, which are released at the site of tissue injury [26, 52, 53]. These act via nerve endings to cause pain impulse formation as well as amplifying further signals caused by direct stimulation [54].
Slow conduction takes place in the visceral unmyelinated C fibers which join somatic nerves and are responsible for referred pain. After entry into the dorsal horn, pain and temperature fibers cross the midline and ascend via the lateral spinothalamic tract. At this level, substance P is the primary mediator. Ascending fibers terminate primarily in the brainstem and thalamus, which then relay the information to the cerebral cortex. Here, the impulse is perceived and localized, and further signals to the limbic system are responsible for the emotional response to pain.
Descending pain fibers from the cerebral cortex and midbrain modulate the afferent nerve stimuli that transmit pain signals to the central nervous system. Enkephalin, norepinephrine, serotonin, and gamma aminobutyric acid (GABA) have been shown to modulate and inhibit the frequency and intensity of nociceptive impulses, thereby attenuating the pain response [28]. Endogenous opioids and endorphins are released from the central nervous system, bind to mu, delta, and kappa opioid receptors, and prevent presynaptic release of neurotransmitters, including substance P. They aslo inhibit the perception and response to painful stimuli.
Both ascending and descending pain pathways can be summarized in Fig. 12.1. Inflammatory pain acts via upregulation of nociceptors and recruiting nonstimulated or dormant receptors [52, 55–57]. Proinflammatory mediators such as IL-1, IL-6, and TNF alpha interferons decrease the threshold for impulse generation and raise the intensity of the impulse as well as the rate of impulse discharge. Further, inflammation perpetuates itself by neurogenic inflammation in which substance P is released and acts peripherally to induce more inflammation, vascular permeability, and ongoing tissue injury [26, 53].
Fig. 12.1
Ascending and descending pathways of nociception (Reproduced with permission from Macres et al. [55])
Neuropathic pain occurs secondary to direct injury of peripheral or central nervous structures, or as a result of compression or tumor invasion. Opioid receptors (mu, kappa, and sigma) exist in the periphery, spinal cord, and central nervous system, as well as inflammatory and immunologic cells [59]. Most receptors are concentrated in the central nervous system, with the highest concentration in the dorsal horn of the spinal cord, periaqueductal gray matter, and rostral ventromedial medulla of the brainstem. Opioids are a mainstay for postoperative and intraoperative analgesia because of their potency. They act by binding to presynaptic receptors and preventing the release of substance P and impulse transmission. The mu receptor is responsible for spinal and supraspinal analgesia as well as having the undesirable side effects of respiratory depression, bowel dysmotility, urinary retention, and pruritis. Kappa, while providing supraspinal and spinal analgesia, also mediates miosis, sedation, and dysphagia. Lastly, the delta receptor mediates spinal and supraspinal analgesia only. A majority of opioids utilized in the perioperative period are mu agonists, having different degree of affinity for mu subtypes. Thus, a “new” opioid may have a different selectivity for the individual mu receptor subtype, explaining “incomplete cross-tolerance” [42]. As a class, opioids do not have a ceiling effect and escalating doses will stop pain once enough opioid is given [54]. The characteristics, pharmacokinetics, and pharmacodynamics of each drug are discussed in other chapters.
Opioid-Induced Hyperalgesia
The chronic pain patient may present perioperatively with an amplified pain response or hyperesthesia. They may also present with allodynia, or pain elicited by a normally non-painful stimulus. Compared to narcotic-naïve patients, opioid-dependent patients have relative pain intolerance and significantly increased sensitivity during cold, pressor, and thermal testing [58, 59]. This is referred to as drug-induced hyperalgesia and is thought to result after continuous opioid receptor occupation. This occurs regardless of route of administration, dosing, and administration schedules [60, 61].
Both central and peripheral neural processes are influenced by the neuronal and humoral inputs caused by nociception [35, 62]. Generally, both types of hyperalgesia share underlying mechanisms mediated by glutamate via the N-methyl-d-aspartate (NMDA) receptor [63, 64]. Because of their amplified pain response, these patients might have extreme difficulty coping with sudden acute pain [11, 58, 65].
Treatment of the Chronic Pain Patient in the Perioperative Period
There are few controlled studies to guide the anesthesiologist in optimizing anesthetic and analgesic care in these patients although the prevalence of opioid dependency continues to increase [2–4, 11, 66]. Scientific literature in this area is mostly case reports and expert opinion. Although these have not been tested specifically, below are guidelines that may serve to improve analgesia and patient satisfaction based on the information we have.
The patient should take their daily maintenance opioid dose before induction of any anesthetic if possible. Most sustained release opioids provide 12 h or more of analgesic effect and should maintain baseline requirements during the preoperative and intraoperative period, particularly for an ambulatory surgery. If the patient forgets or is instructed not to take his or her baseline medication, they should be loaded with an equivalent loading dose of intravenous narcotic at induction or during the procedure. Transdermal fentanyl patches should be maintained. The patient may safely change the patch on their scheduled date if it happens to be the scheduled surgery date without the need for intravenous fentanyl. However, if removed >6–12 h prior this, it can be replaced with an equivalent intravenous maintenance rate. Replacing the patch may take 6–12 h to take full effect and intravenous fentanyl may be weaned after that time [67, 68]. Implanted intrathecal or epidural narcotic infusions are generally continued. If the baseline narcotic requirement is not maintained, withdrawal symptoms may be experienced, as demonstrated by some case reports [34]. While there are many computerized programs and online calculators available to convert various types of oral narcotic dosages to different available types of narcotics via intravenous and intramuscular routes, a narcotic conversion chart may be a useful place to start when calculating baseline opioid requirements (Table 12.5).
Table 12.5
Equianalgesic dosing of opioids for pain management
Druga | Equianalgesic doses (mg) | Approximate equianalgesic 24-h dose (assumes around-the-clock dosing)b | Usual starting dose (adults) (doses not equianalgesic) | |||
|---|---|---|---|---|---|---|
Parenteral | Oral | Parenteral | Oral/other | Parenteral | Oral/other | |
Morphine (immediate-release tablets, oral solution) | 10 | 30 | 3–4 mg q 4 h | 10 mg q 4 h | 2–5 mg q 3–4 h | 5–15 mg q 3–4 h |
Controlled-release morphine (e.g., MS Contin, Kadian) | NA | 30 | NA | 30 mg q 12 h (Kadian may be given as 60 mg q 24 h) | NA | 15 mg q 8–12 h (Kadian may be started at 10–20 mg q 24 h)g |
Extended-release morphine (Avinza [USA], Embeda [with naltrexone USA]) | NA | 30 | NA | 60 mg q 24 h | NA | Avinza: 30 mg q 24 h |
Embeda: 20 mg q 24 h | ||||||
Hydromorphone (Dilaudid) | 1.5–2 | 7.5–8 | 0.5–0.8 mg q 4 h | 2–4 mg q 4 h | See footnotes c,d | See footnote c |
Extended-release hydromorphone (Exalgo, Jurnista [Canada]) | NA | See footnote e | NA | See footnote e | NA | See footnotes f,g |
Oxycodone (e.g., Roxicodone [USA], OxyIR [Canada], also in Percocet, others) | NA | 20–30 | NA | 5–10 mg q 4 h | NA | 5 mg q 3–4 h |
Controlled-release oxycodone (OxyContin) | NA | 20–30 | NA | 20–30 mg q 12 h | NA | 10 mg q 12 h |
Oxymorphone (Opana [USA]) | 1 | 10 | 0.3–0.4 mg q 4 h | 5 mg q 6 h | 0.5 mg q 4–6 h | 10 mg q 4–6 h |
Extended-release oxymorphone (Opana ER [USA])h | NA | 10 | NA | 10 mg q 12 h | NA | 5 mg q 12 h |
Hydrocodone (in Lortab [USA], Vicodin [USA], others) | NA | 30–45 | NA | 10–15 mg q 4 h | NA | 2.5–10 mg q 3–6 h |
Codeine | 100–130 | 200 | 30–50 mg q 4 h | 60 mg q 4 h | 10 mg q 3–4 h | 15–30 mg q 3–4 h |
Methadone (Dolophine [USA], Metadol [Canada]) | Variable | Variable | The conversion ratio of methadone is highly variable depending on factors such as patient tolerance, morphine dose, and length of dosing (short term versus chronic dosing). Because the analgesic duration of action is shorter than the half-life, toxicity due to drug accumulation can occur within 3–5 days (see our detail document “Opioid Dosing”) | |||
Fentanyl | 0.1 | NA | All non-injectable fentanyl products are for opioid-tolerant patients only. Do not convert mcg for mcg among fentanyl products (i.e., patch, transmucosal [Actiq (USA)], buccal [Fentora (USA)], buccal soluble film [Onsolis]). See specific product labeling for dosing | |||
Meperidine (Demerol) | 75 | 300 | Should be used for acute dosing only (short duration of action (2.5–3.5 h)) and neurotoxic metabolite, normeperidine [1]. Avoid in renal insufficiency and use caution in hepatic impairment and in the elderly (potential for toxicity due to accumulation of normeperidine). Seizures, myoclonus, tremor, confusion, and delirium may occur | |||
An equianalgesic dose calculator is available at http://www.hopweb.org
From Therapeutic Research Center [69]
Project leaders in preparation of this detail document: Melanie Cupp, Pharm.D., BCPS (May 2010 update), Jennifer Obenrader, Pharm.D (original author 2004)
NA not available
Equianalgesic doses contained in this chart are approximate and should be used only as a guideline. Dosing must be titrated to individual response. There is often incomplete cross-tolerance among these drugs. It is, therefore, typically necessary to begin with a dose lower (e.g., 25–50 % lower) than the equianalgesic dose when changing drugs and then titrate to an effective response. Dosing adjustments for renal or hepatic insufficiency and other conditions that affect drug metabolism and kinetics may also be necessary. Most of the above opioids are available as generics. Exceptions (with example cost from drugstore.com) include Kadian ($4.81/30 mg cap), Avinza ($4.47/30 mg cap), Opana, Opana ER ($4.40/10 mg tab), Embeda ($4.60/20 mg cap), and Exalgo ($10/8 mg [AWP]). As a comparison, generic morphine controlled release = $1.63/30 mg tab
aTramadol (e.g., Ultram [USA], Ralivia [Canada], potency is about one-tenth that of morphine, similar to codeine. The maximum daily dose of tramadol is 300–400 mg, depending on the product. Also check product information regarding appropriate dosing in elderly or in renal or hepatic dysfunction
bExamples of doses seen in clinical practice, taking into account available dosage strengths
cProduct labeling for hydromorphone recommends a starting dose of 1 mg to 2 mg IV every 4–6 h or 2–4 mg orally every 4–6 h. Some institutions use even lower doses of hydromorphone (e.g., 0.2–0.5 mg every 2 h as needed). One regimen starts opioid-naïve patients at 0.2 mg IV every 2 h as needed for mild or moderate pain, with the option in moderate pain to give an extra 0.2 mg after 15 min if relief is inadequate after the first 0.2-mg dose. For severe pain, 0.5 mg IV every 2 h as needed is used initially. In adults <65 years of age, the 0.5-mg dose can be repeated in 15 min if relief is inadequate, for a maximum of 1 mg in 2 h
dDilaudid Canadian monograph recommends parenteral starting dose of 2 mg. See footnote “c” for additional information and precautions
ePer the product labeling, convert to Exalgo 12 mg from oral codeine 200 mg, hydrocodone 30 mg, morphine 60 mg, oxycodone 30 mg, and oxymorphone 20 mg. The Jurnista product monograph recommends a 5:1 oral morphine to oral hydromorphone conversion ratio
fNo initial dose for Exalgo. For opioid-tolerant patients only. Initial Jurnista dose (opioid naïve or <40 mg daily oral morphine equivalents) is 4–8 mg q 24 h
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