Introduction

Acetaminophen Other generic names include paracetamol and acetylparaaminophenol (APAP). Also referred to as “aspirin-free.”

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, and muscle relaxant) but is analgesic for some painful conditions.

Agonist-antagonist A type of opioid (e.g., nalbuphine and butorphanol) that binds to the kappa opioid receptor site acting as an agonist (capable of producing analgesia) and simultaneously to the mu opioid receptor site acting as an antagonist (reversing mu agonist effects).

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.

Antagonist Drug that competes with agonists for opioid receptor binding sites; can displace agonists, thereby inhibiting their action. Examples include naloxone, naltrexone, and nalmefene.

Bioavailability The extent to which a dose of a drug reaches its site of action.

Blood-brain barrier A barrier that exists between circulating blood and brain, preventing damaging substances from reaching brain tissue and cerebrospinal fluid.

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 (spontaneous or evoked) that is usually associated with neuropathic pain. It is usually described as “pins and needles” (e.g., a limb “falling asleep,” burning, electric shock–like, tingling) and may be intermittent or continuous and experienced in an area of sensory loss. A dysesthesia should always be unpleasant; whereas, a paresthesia should not be 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 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.

Hand-off Communication The process by which nurses share pertinent information about their patients when care is transferred from one nurse to another.

Hydrophilic Readily absorbed in aqueous solution.

Hyperalgesia Increased pain response to noxious stimuli.

Immediate release See short acting.

Incomplete cross-tolerance Because similar drugs (like the mu agonists), have different intrinsic efficacies (how they produce effects after binding to a receptor) at the same receptors, and because each also interacts with a different group of receptor subtypes, a switch from one drug to another similar drug (e.g., from one mu agonist to another) is associated with a variable degree of tolerance to different effects; for example, in an animal model, tolerance to morphine’s analgesic effect can be produced and be made very profound, but analgesia will reappear on switching to another mu agonist like hydromorphone.

Independent double check process An individual, e.g., nurse or pharmacist, checks the analgesic, solution, concentration, dose, and/or programming of analgesic device against the written prescription without prompting from the person administering the analgesic or anyone else. This safety measure is done at specified (by institutional policy) intervals to ensure accuracy of drug delivery, e.g., prior to initiation of IV PCA.

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 Oral opioid 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.

Mu agonist Any opioid that binds to the mu opioid receptor subtype and produces effects. Includes morphine and other opioids that relieve pain by binding to the mu receptor sites in the nervous system. Used interchangeably with the terms full agonist, pure agonist, and morphine-like drug.

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 sustained by injury or dysfunction of the peripheral or central nervous systems.

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).

Normal release See short acting.

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 the opioid, including analgesia and sedation, but there is no timeframe 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 definition of 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).

Pseudoaddiction A mistaken diagnosis of addiction in which patients exhibit behaviors often seen in addictive disease, such as escalating demands for larger doses of opioids, but actually reflect undertreated pain; may co-exist with the disease of addiction and drive relapse behaviors.

Refractory Nonresponsive or resistant to therapeutic interventions such as first- and 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.

Short acting Oral opioid analgesics with a relatively fast onset of action (e.g., 30 minutes) and short duration (3 to 4 hours) and often referred to a “normal release” and inaccurately as “immediate release.” The term immediate release is particularly problematic because none of the oral opioid analgesics have an immediate onset of action. The term short acting will be used in this book.

Supraspinal Involving the brainstem or cerebrum.

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.

Upregulation An increase in a cellular component, e.g., increase in the number of receptors making 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 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 of 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 what treatment conditions to which subjects are assigned, but subjects are “blinded” (not aware) of what they are receiving.