Acetaminophen Other generic names include paracetamol and acetylparaaminophenol (APAP). Also referred to as “aspirin-free” drugs.
Addiction A chronic neurologic and biologic disease. As defined by pain specialists, it is characterized by behaviors that include one or more of the following: impaired control over drug use, compulsive use, continued use despite harm, and craving. Continued craving for an opioid and the need to use the opioid for effects other than pain relief. Physical dependence and tolerance are not the same as addiction.
Adjuvant analgesic A drug that has a primary indication other than pain (e.g., anticonvulsant, antidepressant, sodium channel blocker, or muscle relaxant) but is analgesic for some painful conditions.
Allodynia Pain due to a stimulus that does not normally provoke pain, such as touch. Typically experienced in the skin around areas affected by nerve injury; commonly seen with many neuropathic pain syndromes.
Analgesic ceiling A dose beyond which further increases in dose do not provide additional analgesia.
Bioavailability The extent to which a dose of a drug reaches its site of action.
Breakthrough dose (BTD) Also referred to as supplemental dose or rescue dose; the dose of analgesic taken to treat breakthrough pain.
Breakthrough pain (BTP) A transitory increase in pain that occurs on a background of otherwise controlled persistent pain.
Ceiling effect A dose above which further dose increments produce no change in effect.
Comfort-function goal The pain rating identified by the individual patient above which the patient experiences interference with function and quality of life, that is, activities that the patient needs or wishes to perform.
Controlled release See modified release.
Crescendo pain A period of rapid pain escalation often associated with increasing distress and functional impairment.
Distribution half-life The time it takes a drug to move from the blood and plasma to other tissues. Distribution half-life differs from half-life (terminal) (see half-life).
Dysesthesia An unpleasant abnormal sensation (whether spontaneous or evoked) that is usually associated with neuropathic pain and described as “pins and needles” (e.g., a limb “falling asleep,” burning, electrical shock–like, tingling) and may be intermittent or continuous and experienced in an area of sensory loss. A dysesthesia is always unpleasant, whereas a paresthesia is not unpleasant. It may be difficult to differentiate dysesthesias from paresthesias.
Efficacy The extent to which a drug or another treatment “works” and can produce the effect in question—analgesia in this context. To determine whether or not this is the case, the treatment must be compared to another, typically a placebo, but sometimes an active comparator. Maximal efficacy refers to the maximum effect that can be produced by a drug, and comparative efficacy refers to the relative effects of two or more treatments compared at comparable treatment intensities.
Extended release See modified release.
Half-life The time it takes for the plasma concentration (amount of drug in the body) to be reduced by 50%. After starting a drug, or increasing its dose, four to five half-lives are required to approach a steady-state level in the blood, irrespective of the dose, dosing interval, or route of administration; after four to five half-lives, a drug that has been discontinued generally is considered to be mostly eliminated from the body.
Hydrophilic Readily absorbed in aqueous solution.
Hyperalgesia Increased pain response to noxious stimuli.
Intractable In reference to pain that is unresponsive to all other recommended therapeutic options (e.g., first-line and second-line analgesics).
Intraspinal “Within the spine”; term referring to the spaces or potential spaces surrounding the spinal cord into which medications can be administered. Most often, the term is used when referring to the epidural and intrathecal routes of administration. Sometimes used interchangeably with the term neuraxial.
Lipophilic Readily absorbed in fatty tissues.
Medically ill patients Patients with existing debilitating pathologic condition/illness that may be progressive or stable, as opposed to those who have only the symptom of pain and are otherwise healthy.
Metabolite The product of biochemical reactions during drug metabolism.
Modified release Analgesics that are formulated to release over a prolonged period of time; often used interchangeably with the terms extended release, sustained release, and controlled release. The term modified release will be used in this book to describe these drugs.
Narcotic See opioid. Obsolete term for opioid, in part because the government and media use the term loosely to refer to a variety of substances of potential abuse. Legally, controlled substances classified as narcotics include opioids, cocaine, and various other substances.
Neuralgia Pain in the distribution of a nerve (e.g., sciatica, trigeminal neuralgia). Often felt as an electrical shock–like pain.
Neuropathic pain Pain that is sustained by injury or dysfunction of the peripheral or central nervous system.
NMDA N-methyl-d-aspartate. In this book, the term is used in conjunction with drugs that are NMDA receptor antagonists or blockers, such as ketamine or dextromethorphan.
Nociceptive pain Pain that is sustained by ongoing activation of the sensory system that subserves the perception of noxious stimuli; implies the existence of damage to somatic or visceral tissues sufficient to activate the nociceptive system.
Nociceptor A primary afferent nerve that has the ability to respond to a noxious stimulus or to a stimulus that would be noxious if prolonged.
Nonopioid Used instead of nonnarcotic. Refers to acetaminophen and nonsteroidal antiinflammatory drugs (NSAIDs).
NSAID An acronym for nonsteroidal antiinflammatory drug. (Pronounced “in said.”) Also referred to as aspirin-like drugs.
Opioid This term is preferred to narcotic. Opioid refers to codeine, morphine, and other natural, semisynthetic, and synthetic drugs that relieve pain by binding to multiple types of opioid receptors.
Opioid dose-sparing effect The dose of opioid may be lowered when another analgesic, such as a nonopioid, is added.
Opioid-induced hyperalgesia (OIH) A phenomenon clearly demonstrated in experimental models, but of uncertain significance in humans, by which exposure to the opioid induces increased sensitivity, or a lowered threshold, to the neural activity subserving pain perception; it is the “flip side” of analgesic tolerance, which is defined by the loss of analgesic activity due to exposure to the drug.
Opioid-naïve An opioid-naïve person has not recently taken enough opioid on a regular enough basis to become tolerant to the effects of an opioid.
Opioid-tolerant An opioid-tolerant person has taken opioids long enough at doses high enough to develop tolerance to many of the effects of an opioid, including analgesia and sedation, but there is no time frame for developing tolerance.
Paresthesia An abnormal sensation, whether spontaneous or evoked, manifested by sensations of numbness, prickling, tingling, and heightened sensitivity that is typically not unpleasant.
Paroxysmal Sudden periodic attack or recurrence.
Physical dependence Potential for withdrawal symptoms if the opioid is abruptly stopped or an antagonist is administered; not the same as addiction.
Potency The dose required to produce a specified effect; relative potency is the ratio of the doses of two or more analgesics required to produce the same analgesic effect.
Preemptive analgesia Preinjury pain treatments (e.g., preoperative epidural analgesia and preincision local anesthetic infiltration) to prevent the establishment of peripheral and central sensitization of pain.
Primary afferent neuron See nociceptor.
Prodrug An inactive precursor of a drug, converted into its active form in the body by normal metabolic processes.
Protective analgesia An aggressive, sustained multimodal intervention administered perioperatively (e.g., local anesthetic block, acetaminophen, NSAID, and anticonvulsant initiated preoperatively and continued throughout the intraoperative and postoperative periods) and directed toward prevention of pathologic pain (e.g., persistent neuropathic postsurgical pain syndromes).
Refractory Nonresponsive or resistant to therapeutic interventions such as first-line or second-line analgesics.
Rescue dose Also referred to as supplemental dose or breakthrough dose. Administered on a PRN basis (as needed) in combination with the regularly scheduled analgesic to relieve pain that exceeds, or breaks through, the ongoing pain.
Sustained release See modified release.
Systemic drug treatment; systemic administration Administration of a drug by a given route that allows absorption into the systemic circulation. Routes include oral, parenteral (IV, IM, SC), rectal, vaginal, topical application, transdermal, intranasal, and transmucosal. By contrast, the spinal route of administration deposits the drug directly into the central nervous system, minimizing the amount of drug that reaches the systemic circulation.
Titration Adjusting the amount (e.g., adjusting the dose of opioid).
Tolerance A process characterized by decreasing effects of a drug at its previous dose, or the need for a higher dose of drug to maintain an effect; not the same as addiction.
Up-regulation An increase in a cellular component (e.g., an increase in the number of receptors) that makes the cells more sensitive to a particular drug or other agent.
Anecdotal evidence Evidence derived from clinical observations, clinical experience, or published case reports.
Case reports Published reports of one or more patient cases describing patient experiences, circumstances, or situations that infer specific outcomes that are not based on any scientific method of study.
Case-control study A retrospective observational study used most often to evaluate risk factors that may help explain the appearance or presentation of a disease or condition. Subjects with a known disease or condition are matched with similar individuals who do not possess it. Various potential risk factors, such as age or sex, or lifestyle factors, are then statistically evaluated to determine their levels of association with the disease or condition.
Cohort study A retrospective or prospective study in which a group of subjects who have a specific condition or receive a particular treatment are evaluated over time for a defined period. Data may be compared with another group of subjects who do not have the same condition or receive the same treatment, or subgroups within the cohort may be compared.
Controlled studies/trials Research studies that exert some or total control over the various treatment effects by using a comparison group (placebo group or comparator treatment group) and may use a single- or double-blind design, or a random assignment of subjects.
Double-blind study Neither the investigator nor the subject know the critical aspects of the study (e.g., in a placebo-controlled trial, neither the person administering the intervention nor the subject receiving the intervention know if the intervention is experimental or placebo); used to reduce investigator and subject bias.
Meta-analysis Data analysis in which the results of several studies that address related research are combined and analyzed to arrive at one overall measurement of treatment effect.
Number needed to treat (NNT) A parameter that is often used in reporting the results of epidemiologic studies, clinical trials, systematic reviews, and meta-analyses. It is an estimate of how many people would need to receive an intervention to prevent one undesirable outcome or how many people need to receive a treatment in order that one derives a well-defined benefit (e.g., a 50% reduction in pain). NNT is calculated by using a formula that involves a known risk reduction or benefit analysis. Investigators typically determine and define the outcome that is used to compute the NNT for their study.
Open-label Both the investigators and the subjects know what treatment subjects are receiving. An investigator studies the response to an analgesic in a sample of patients and follows them through the treatment phase, observing and recording the effects. A disadvantage of this study design is potential bias for patient selection, observations, and conclusions.
Placebo-controlled trial A study that compares a treatment to a placebo, which is a treatment with no known therapeutic value. The placebo typically resembles the active intervention and is used as the control to determine the active intervention’s efficacy.
Randomized controlled trial (RCT) A study in which subjects are randomly assigned (by chance alone) to receive the various interventions in a study. Randomization increases the likelihood that factors that could influence the effects produced by a treatment are distributed evenly across treatment groups, thereby limiting the risk of bias.
Relative risk (RR) A measure of the risk of a certain event happening in one group compared with the risk of the same event happening in another group. For example, in cancer research, relative risk is used in prospective (forward-looking) studies, such as cohort studies and clinical trials. A relative risk of 1 means there is no difference between groups in terms of their risk of cancer, based on whether or not they were exposed to a certain substance or factor, or how they responded to two treatments being compared. A relative risk greater than 1 or less than 1 means that being exposed to a certain substance or factor either increases (relative risk greater than 1) or decreases (relative risk less than 1) the risk of cancer, or that the treatments being compared do not have the same effects (e.g., a relative risk of 2 would mean that those exposed to a certain substance or factor have twice the risk of cancer compared with those who are not exposed to a certain substance or factor). Relative risk is also often called relative ratio.
Sequential trials One drug is tried and if the results are unfavorable, it is discontinued and another drug is tried. A trial-and-error approach in which one drug after another is tried until the desired effects occur.
Single-blind study The investigators know to what treatment conditions subjects are assigned, but subjects are “blinded” (not aware) of what they are receiving.
The term adjuvant analgesic describes any drug that has a primary indication other than for pain but is analgesic for some painful conditions. This term, while widely accepted, is actually now a misnomer. Some adjuvant analgesics are indicated for specific types of pain, and, in this context, are not “adjuvant” to some other primary therapy. The adjuvant analgesics, therefore, are better considered nontraditional pain relievers that can be used both as “add-on” therapy to an opioid regimen or as distinct primary therapy for specific painful disorders.
More generally, adjuvant analgesics may be distinguished from “adjuvant therapy,” which also has a different meaning in some contexts. For example, in the palliative care literature, adjuvant therapies comprise both analgesics (which may be combined with nonopioid analgesics, such as the NSAIDs, into a grouping called coanalgesics) and drugs used to counteract the adverse effects of analgesics. In this literature, emphasis is given to the treatment of pain using combination therapy consisting of opioids combined with coanalgesics and other drugs to manage opioid adverse effects; the adjuvant analgesics (e.g., antidepressants, anticonvulsants, corticosteroids, or bisphosphonates) are used to enhance opioid pain relief, treat pain less responsive or refractory to opioids, or reduce the doses of opioids to limit adverse effects (Ferrell, Levy, Paice, 2008; Klepstad, Kaasa, Cherny, et al., 2005; Lussier, Portenoy, 2004).
Clinical experience with most of the adjuvant analgesics initially evolved from the treatment of persistent neuropathic pain (see Section I); however, the role of adjuvant analgesics has expanded to include other types of persistent (chronic) pain syndromes as well as acute pain from surgery, trauma, or burns. For persistent pain unrelated to cancer or other progressive diseases, adjuvant analgesics are often used alone—not as an adjuvant to any other pharmacologic therapy. Some adjuvant analgesics are potentially useful for a variety of painful disorders (they may be considered multipurpose analgesics), and others are used for specific pain disorders because the literature is limited or they exert an action that targets a particular pain mechanism (Portenoy, 2000). The practice of administering adjuvant agents as primary analgesics has gained widespread acceptance in the treatment of some types of persistent noncancer pain, such as fibromyalgia, painful diabetic neuropathy, and postherpetic neuralgia.
Considerable research is underway to examine the role of adjuvant analgesics and to determine their benefits in the armamentarium of therapeutics for the treatment of pain. This section focuses on the knowledge, clinical experience, research, and evidence that are available to support the use of adjuvant analgesics in a wide range of painful conditions. Although there are still significant gaps in the evidence supporting the role of these drugs as analgesics, significant progress has been made in drug development and testing, in establishing indications for new and existing adjuvant analgesics, and in positioning these therapies through a growing clinical experience.
Various research terms are applied to discussions of investigations on adjuvant therapies, and these are defined in the glossary of terms appearing in the beginning of this section (Terminology). See also Table 3-4 (p. 130) for more research definitions. These definitions help to enhance the understanding of published studies and reports pertaining to adjuvant therapy and enable clinicians to evaluate the relative strength of evidence currently available. For example, clinical observations of astute clinicians, often referred to as anecdotal evidence, and guidelines derived largely from observational studies, anecdotal reports, and expert consensus can make valuable contributions to practice when research is inconclusive. Evidence-based guidelines developed from the data generated by randomized, placebo-controlled, double-blind studies, and especially from the systematic reviews or meta-analyses that may be done if the number of studies is sufficient, usually are more convincing and provide considerably stronger evidence to guide treatment decisions.
Adjuvant analgesics compose an extraordinarily diverse group of drug classes. A generally useful, broad classification distinguishes those that may be considered nonspecific, multipurpose analgesics from those that have more specific indications for selected types of pain (pp. 627-628). The availability of these drugs helps promote the concept of multimodal analgesia and effective symptom management. Growing research has dispelled common misconceptions about these drugs (table on pp. 627-628). Major classes of adjuvant analgesics, along with examples, are listed in the Adjuvant Analgesics table (pp. 628-630). The appropriate use of any of the analgesics discussed in this book requires an understanding of the underlying mechanisms of pain and analgesics. The reader is referred to Section I for a detailed discussion of the underlying mechanisms of nociceptive (physiologic) pain and the pathophysiology of neuropathic pain.
Common Misconceptions about Adjuvant Analgesics
| Misconception | Correction |
| Adjuvant analgesics are as reliable in providing pain relief as opioid and nonopioid analgesics. | Fewer patients respond adequately to adjuvant analgesics than to opioids and nonopioids. Furthermore, many adjuvant analgesics tend to have a much slower onset of analgesia and more adverse effects. |
| Adjuvants are only effective for neuropathic pain. | Some adjuvant analgesics such as antidepressants, corticosteroids, alpha2-adrenergic agonists (e.g., clonidine), and cannabinoids are multipurpose analgesics that may be useful for both neuropathic and nociceptive (somatic and visceral) pain. |
| Adjuvant analgesics are appropriate only for persistent (chronic), not acute, pain. | There is growing evidence to support the role of adjuvant analgesics (e.g., anticonvulsants, sodium channel blockers, ketamine) in the treatment of both acute and persistent pain. |
| Use of adjuvant analgesics is no more time-consuming than use of other analgesic groups. | Drug selection and dose titration of adjuvants are usually more challenging and “labor intensive” than administration of opioid and nonopioid analgesics. |
| Pain relief from antidepressants depends on their ability to relieve depression in the patient with pain. | The analgesic effects of antidepressants are independent of their antidepressant activity. Patients who are depressed and those who are not depressed with pain report analgesia. Furthermore, the analgesic dose is often lower than that required to treat depression, and the onset of analgesia typically occurs much sooner, usually within 1 week. |
| Antidepressants are more appropriate analgesics for burning neuropathic pain than for stabbing and lancinating (knifelike) neuropathic pain. | Research shows that antidepressants may be effective for both lancinating (knifelike) and continuous neuropathic pain. |
| Anticonvulsants are only used for persistent neuropathic pain. | Anticonvulsants now have a role in the treatment of acute pain, such as postoperative pain and prevention of persistent neuropathic postsurgical pain, as well as persistent mixed pain syndromes, such as fibromyalgia and some back pain. |
| Topical analgesics relieve only superficial pain. | Topical analgesics, such as lidocaine patch 5% and capsaicin, have been shown to be effective in relieving a variety of types of pain including some types of neuropathic pain. |
| Sedation alone is sufficient for painful procedures. | The low doses of sedative agents used for procedural sedation do not produce sufficient pain relief or entirely eliminate the memory of pain during the procedure. Sedation protocols for procedures thought to be painful should include the provision of analgesia regardless of the amnestic qualities of the sedative agent. |
| Drugs marketed as muscle relaxants, such as methocarbamol (Robaxin), relieve muscle pain by relaxing the muscle. | Well-controlled research is lacking to demonstrate that “muscle relaxants” relax skeletal muscle in humans. Although these drugs can relieve musculoskeletal pain, this may not be due to relaxation of skeletal muscle. |
From Pasero, C., & McCaffery, M. Pain assessment and pharmacologic management, pp. 627-628, St. Louis, Mosby. Pasero C, McCaffery M. May be duplicated for use in clinical practice.
Adjuvant Analgesics: Major Classes and Examples of Drugs
| Pharmacologic Class/Generic Drug Names | Brand Name |
| Alpha2-Adrenergic Agonists Clonidine |
Catapres, Catapres TTS, Duraclon |
| Dexmedetomidine | Precedex |
| Tizanidine | Zanaflex |
| Anticonvulsants Carbamazepine |
Tegretol |
| Clonazepam | Klonopin |
| Divalproex sodium | Depakote Sprinkle, Depakote DR, ER |
| Gabapentin | Neurontin |
| Lacosamide | Vimpat |
| Lamotrigine | Lamictal |
| Oxcarbazepine | Trileptal |
| Phenytoin | Dilantin |
| Pregabalin | Lyrica |
| Tiagabine | Gabitril |
| Topiramate | Topamax |
| Valproic acid | Depacon (IV), Depakene (PO), Stavzor DR (PO), Valproate Sodium (IV) (valproates include divalproex sodium and valproic acid) |
| Zonisamide | Zonegran |
| Antidepressants Amitriptyline |
Elavil |
| Bupropion | Aplenzin, Budeprion, Wellbutrin |
| Clomipramine | Anafranil |
| Desipramine | Norpramin |
| Doxepin | Sinequan |
| Duloxetine | Cymbalta |
| Fluoxetine | Prozac |
| Imipramine | Tofranil |
| Maprotiline | Ludiomil |
| Milnacipran | Savella |
| Mirtazapine | Remeron |
| Nefazodone | Serzone |
| Nortriptyline | Aventyl, Pamelor |
| Paroxetine | Paxil |
| Sertraline | Zoloft |
| Trazodone | Desyrel |
| Venlafaxine | Effexor |
| Cannabinoids Cannabis derivative |
Sativex |
| Dronabinol | Marinol |
| Corticosteroids Dexamethasone |
Baycadron, Decadron, Dexamethasone Intensol |
| Methylprednisolone | Depo-Medrol, Medrol, Solu-Medrol |
| Prednisone | Sterapred, Sterapred DS, Prednisone Intensol |
| Gamma Aminobutyric Acid (GABA) Agonists Baclofen |
Lioresal |
| Fospropofol | Lusedra |
| Propofol | Diprivan |
| Sodium Channel Blockers Flecainide |
Tambocor |
| Lidocaine (IV) | Lidocaine |
| Lidocaine patch 5% | Lidoderm |
| Mexiletine | Mexitil |
| Tocainide | Tonocard |
| N-methyl-d-Aspartate (NMDA) Receptor Antagonists Dextromethorphan |
Delsym, Robafin Cough, Robitussin CoughGels |
| Ketamine | Ketalar |
| Neuroleptics Haloperidol |
Haldol |
| Olanzapine | Zyprexa, Zydis |
| Pimozide | Orap |
| Psychostimulants Dextroamphetamine |
Dexedrine |
| Methylphenidate | Concerta, Daytrana, Metadate, Methylin, Ritalin |
| Modafinil | Provigil |
| Skeletal “Muscle Relaxants” Carisoprodol |
Soma |
| Chlorzoxazone | Parafon Forte DSC |
| Cyclobenzaprine | Flexeril |
| Methocarbamol | Robaxin |
| Orphenadrine | Norflex |
| Topical Agents Antidepressants (amitriptyline; doxepin) (compounded) |
Elavil; Sinequan |
| Anticonvulsants (clonazepam) (compounded) | Klonopin |
| Capsaicin | Arthritis Formula Capiscum; Capzasin; Trixaicin; Zostrix; others |
| Clonidine | Catapres TTS |
| Ketamine (compounded) | Ketalar |
| Local anesthetics | EMLA; Lidoderm, L.M.X.4; Synera |
From Pasero, C., & McCaffery, M. Pain assessment and pharmacologic management, pp. 628-630, St. Louis, Mosby. Pasero C, McCaffery M. May be duplicated for use in clinical practice.