Introduction

Chris Pasero, Russell K. Portenoy and Margo McCaffery

Terminology

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.

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 This consists of 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.

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).

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 sometime 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.

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).

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.

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.

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

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 the opioid, including analgesia and sedation, but there is no timeframe for developing tolerance.

Physical dependence Potential for withdrawal symptoms if the opioid is abruptly stopped or an antagonist is administered.

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).

Refractory Nonresponsive or resistant to therapeutic interventions such as 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.

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, 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.

Terminology Related to Research

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 subjects are assigned to, but subjects are “blinded” (not aware) of what they are receiving.

In clinical practice, analgesics may be divided into three groups: nonopioids, opioids, and the so-called “adjuvant” analgesics. This section focuses on the nonopioid analgesics, specifically acetaminophen and the nonsteroidal antiinflammatory drugs (NSAIDs) (see Section IV for opioid analgesics and Section V for adjuvant analgesics). These drugs all are both analgesic and antipyretic, and the NSAIDs are antiinflammatory. They share many of the same effects, but they are a mixed group and contain drugs that differ in chemical structure and adverse effect profiles.

Although all nonopioids sometimes are loosely referred to as NSAIDs, acetaminophen should not be classified this way. Acetaminophen should be distinguished from NSAIDs because it seems to relieve pain by different mechanisms and has minimal antiinflammatory effect. Acetaminophen may be referred to as an aspirin-free drug, whereas NSAIDs may be termed aspirin-like drugs. Other generic names for acetaminophen are APAP (acetylparaaminophenol) and paracetamol. You may wish to review some of the misconceptions about nonopioids on the next page.

Misconceptions about Nonopioids

Misconception Correction
Regular daily use of nonopioids is much safer than taking opioids long-term. Adverse effects from long-term use of NSAIDs are considerably more severe and life threatening than the adverse effects of daily doses of opioids. The most common adverse effect of long-term use of opioids is constipation, whereas NSAIDs can cause gastric ulcers, increased bleeding time, and cardiovascular adverse events. Acetaminophen can cause hepatotoxicity.
Nonopioids are not useful analgesics for severe pain. Nonopioids alone are rarely sufficient to relieve severe pain, but they are an important part of a multimodal analgesic plan. One of the basic principles of analgesic therapy is: Whenever pain is severe enough to require an opioid, adding nonopioids (acetaminophen and NSAID) should be considered.
It is unacceptable polypharmacy to administer an NSAID, opioid, and one or more adjuvant analgesics (e.g., local anesthetic, anticonvulsant, antidepressant) for pain control. Analgesics within each of the three analgesic groups relieve pain by different mechanisms. It is acceptable and, in most cases, recommended rational polypharmacy to administer more than one drug if each one is for a specific purpose.
A nonopioid should not be given at the same time as an opioid. It is safe to administer a nonopioid and opioid at the same time. Giving a dose of nonopioid at the same time as a dose of opioid poses no more danger than giving the doses at different times. In fact, many opioids are compounded with a nonopioid (e.g., Percocet [oxycodone and acetaminophen]).
Administering NSAIDs rectally or parenterally prevents gastric ulcers. Regardless of the route of administration, NSAIDs inhibit prostaglandins (PGs) that are necessary to maintain the protective barrier in the GI tract. Rectal or parenteral administration will only avoid the local irritation that can occur with oral administration.
Topical nonopioids are not effective analgesics. Topical nonopioids have been shown to produce effective analgesia for mild to moderate acute or persistent (chronic) pain with a lower incidence of GI adverse effects.
Administering antacids with NSAIDs is an effective method of reducing gastric distress. Administering antacids with NSAIDs can lessen distress but may be counterproductive. Antacids reduce the absorption and therefore the effectiveness of the NSAID by releasing the drug in the stomach rather than in the small intestine where absorption occurs.
For patients receiving long-term treatment with NSAIDs, H2 blockers such as cimetidine (Tagamet) provide effective protection against gastric and duodenal ulcers. H2 blockers at higher than standard doses may be helpful, but misoprostol (Cytotec) and proton pump inhibitors (PPIs) such as esomeprazole (Nexium), lansoprazole (Prevacid), and omeprazole (Prilosec), are more effective and the only proven methods to reduce the occurrence of gastric and duodenal ulcers.
Gastric distress (e.g., abdominal pain) is indicative of NSAID-induced gastric ulceration. Most patients with gastric lesions have no symptoms until bleeding or perforation occurs.
NSAIDs affect bone healing and should not be taken following orthopedic surgery. Withdrawal of COX-2 inhibition when NSAIDs are discontinued after a short-term course (10 to 14 days) restores normal bone healing with no discernible effects on fracture healing (see text for exceptions and references).

From Pasero, C., & McCaffery, M. Pain assessment and pharmacologic management, p. 180, St. Louis, Mosby. Pasero C, McCaffery M. May be duplicated for use in clinical practice.