Terminology and Subtypes

The term opioid analgesics refers to medications that act on opioid receptors and are used for pain relief. Although the term narcotic has also been used to describe these medications in the past, opioid analgesic is the preferred term now that the word narcotic has taken on negative connotations.¹ The term weak (or weaker) opioid analgesics is sometimes used to refer to compound medications combining simple analgesics such as acetaminophen with low doses of codeine or tramadol. Moderate or strong (or stronger) opioid analgesics, by definition, exclude weak opioid analgesics. The terms mild and major are also occasionally used to differentiate weaker opioids from stronger opioids. Other methods of classifying opioids have been proposed based on their origins (i.e. endogenous, opium alkaloids, semi-synthetic, fully synthetic) or effects on receptors (i.e. full/partial/mixed agonists). Regardless of how they are classified, opioids may also be compared in terms of relative strength by using tables that estimate equivalence doses for different opioids.

Opioid analgesics can be divided into three categories: sustained-release opioids (SROs), immediate-release opioids (IROs), and long-acting opioids (LAOs).^2,3 SROs are also known as continuous release (CR) or extended release (ER), and release medication continuously from the gastrointestinal (GI) tract after ingestion or transdermally via a reservoir; they are therefore used for continuous pain control. SROs include medications such as morphine-ER, oxycodone-CR, oxymorphone-ER, and transdermal fentanyl (TDF). IROs have a rapid onset of analgesia, are short acting, are used for breakthrough pain or acute pain, and include medications such as oxycodone-IR, hydrocodone, and morphine sulfate-IR. LAOs are taken according to a regular dosing schedule to minimize fluctuation in effective concentrations and include medications such as methadone and levorphanol.

Although the terms addiction and dependence are often used interchangeably, their meanings are very different. Addiction refers to a neurobiologic disease with genetic, psychosocial, and environmental factors characterized by behaviors that include the compulsive use of a psychoactive substance despite the harms endured; it involves loss of control. Dependence is a state of physiologic adaptation induced by the chronic use of any psychoactive substance, and can occur independently of any addiction.⁴ Addiction is always a clinical problem, whereas dependence is not.^5,6 The term pseudoaddiction is sometimes used to describe a scenario in which patients seek additional medications because their current pain relief is not adequate.⁷

In this context, severe episodes of pain not controlled by usual pain medication are termed breakthrough pain. The term diversion indicates that medications legitimately prescribed by physicians are appropriated, voluntarily or otherwise, and used by others.

History and Frequency of Use

In patients with severe pain related to cancer, opioid analgesics have been considered the standard of care for pain management for many years, despite the lack of high-quality evidence supporting either efficacy or safety with long-term use. For severe pain not related to cancer, there has long been a bias by many physicians in North America against prescribing opioid analgesics. This perception is likely due to misinformation among physicians about adverse events related to opioid analgesics, regulation and monitoring of certain opioid analgesics, and a lack of understanding about the impact of severe pain on quality of life.⁸ This position has slowly been changing in recent decades, perhaps due to legislation in certain states in the US mandating continuing medical education about chronic pain (e.g., California). Studies began to appear approximately 10 years ago that suggested opioid analgesics could be both safe and effective in well-selected patients with chronic low back pain (CLBP).^9,10 Today, many spine centers offer opioid analgesics to patients with moderate or severe CLBP refractory to other medications or interventions (Table 12-1).^9,11,12

TABLE 12-1 Opioid Analgesics Commonly Used for Chronic Low Back Pain

A study was conducted to examine health care utilization in patients with mechanical low back pain (LBP) as defined by one of 66 related ICD-9 codes.¹³ Data were obtained from utilization records of Kaiser Permanente Colorado, a health maintenance organization with 410,000 enrollees in the Denver area. Pharmacy records indicated that 29% of patients had a claim for opioids. A study was conducted to estimate the direct medical costs focusing on analgesic medication used for mechanical LBP as defined by one of 66 ICD-9 codes.¹³ Data were obtained from utilization records of 255,958 commercial members enrolled in the University of Pittsburgh Medical Center Health System in 2001. Among the 9417 patients (56%) with a pharmacy claim for analgesics related to their LBP, the most frequent analgesic was opioids (33%), followed by opioids and NSAIDs (26%), and opioid and other analgesics (9%). Most opioid use was short-term, with a duration of 1 to 30 days (71%), although a substantial portion had a duration of 31 to 90 days (14%). Smaller proportions of patients used opioids for 90 to 179 days (6%), and more than 180 days (9%). In specialty spine practices, opioids were part of the plan after a single visit for 3% of more than 25,000 patients, 75% of whom had pain for longer than 3 months.¹²

In a university orthopedic spine clinic, opioids were prescribed for 66% of patients and 25% received long-term opioid (LTO) treatment.¹¹ It has been reported that the proportion of patients receiving opioid analgesics is higher in secondary care settings than in primary care settings and that those with poor physical function and greater distress were more likely to receive them.¹⁴ In a retrospective study of 165,569 employees covered by three large employer-sponsored health plans in the United States, almost half (45%) of the 13,760 patients who had reported LBP had claims for opioid analgesics in the previous year.¹⁵ Factors associated with an increased use of opioid analgesics included comorbidities such as hypertension, arthritis, depression, anxiety, cancer, and prior surgery.

Practitioner, Setting, and Availability

A physician is required to administer this intervention because these medications are only available by prescription. Although any licensed physician can prescribe opioids, pain management specialists are generally more comfortable monitoring patients who require this type of therapy than general practitioners, and they are more experienced at titrating the dose and other medication requirements. Patients may consult physicians for this therapy in a variety of settings (outpatient pain centers, private pain clinics, private physician offices) and locations. This treatment is widely available across the United States, although specialty spine pain clinics tend to be located in larger cities.

Procedure

Management of CLBP with opioid analgesics involves a consultation with a physician who will take a detailed medical and LBP-focused history, and inquire about current medication use. If deemed appropriate, the physician will then prescribe one or more opioid analgesics along with instructions about dosage, timing, side effects, and interactions with other medication; this information may also be provided by the dispensing pharmacist. A follow-up appointment will likely be scheduled within a few days so that the physician can determine whether the opioid analgesic is achieving the desired effect, adjust the dosage if necessary, change the medication in favor of another opioid analgesic or different class of medication if required, and provide education about other strategies for improving CLBP.

There are two ways to dose opioid analgesics: pain-contingent or time-contingent. Pain-contingent dosing is defined as medication taken when pain occurs (as needed), whereas time-contingent dosing is defined as medication taken on a regular schedule based on the duration of analgesia rather than intensity of symptoms at that time (by the clock). Based on the authors’ clinical experience managing patients with CLBP, it appears that time-contingent dosing of opioids generally provides better long-term pain control, fewer side effects, and improved compliance when compared to pain-contingent use. SROs or LAOs are typically taken on a time-contingent basis, whereas IROs are taken on a pain-contingent basis. The duration of action of SROs and LAOs is somewhat variable, and depends on rates of absorption, distribution, metabolism, and excretion (ADME). Many patients require dosing intervals that are shorter than generic manufacturer recommendations.^16,17 An IRO may be prescribed for breakthrough pain in those taking SROs or LAOs.

An occasional patient may experience better pain control with an IRO administered on a time-contingent basis than with SROs or LAOs. It is not uncommon for the physician to have to try several different opioid analgesics to identify which one is best for a particular patient. An individual patient’s response is at least in part based on a genetic predisposition¹⁸; some CLBP patients may not respond to opioid analgesics at all, despite trying different medications. There is no universally correct dose of opioid analgesics for CLBP; treatment should be initiated at conservative doses until patient response can be assessed. Both the dose and the dosing schedule must be titrated for each patient according to analgesic efficacy and side effects. Most opioids do not have a true ceiling effect and therefore have no maximum dose. However, side effects increase with dose and can interfere with improvements associated with analgesia.

General guidelines for the use of opioid analgesics are summarized in Table 12-2. Specific guidelines for individual medications are summarized here.

TABLE 12-2 General Recommendations for the Use of Opioid Analgesics in the Treatment of Chronic Pain

Regulatory Status

The opioid analgesics discussed in this chapter are all approved by the US Food and Drug Administration for primary indications related to pain, although not specifically CLBP. These medications are only available by prescription, and many are subject to additional monitoring required for controlled substances (Figure 12-1).

Figure 12-1 Opioid analgesics are only available by prescription.

(© Gold Standard, Inc.)

Mechanism of Action

The analgesic effects of opioids are thought to be related to their ability to bind opioid receptors, which are located primarily in the central nervous system (CNS) and GI system (Figure 12-2). Different medications are thought to exhibit different affinities for specific opioid receptors, including the main µ (mu), κ (kappa), and δ (delta) opioid receptors.⁵ Binding to opioid receptors is thought to inhibit transmission of nociceptive input from the peripheral nervous system (PNS), activate descending pathways that modulate and inhibit transmission of nociceptive input along the spinal cord, and also alter brain activity to moderate responses to nociceptive input.³⁵ As new opioid receptors are discovered and the properties of known opioid receptors are better understood, additional medications may be developed to selectively act on specific receptors to improve efficacy or decrease side effects (Figure 12-3).

Figure 12-2 Mechanism of action for opioid analgesics (e.g., morphine).

(Modified from Wecker L: Brody’s human pharmacology, ed. 5. St. Louis, 2010, Mosby.)

Figure 12-3 Molecular structure of medications with different effects on opioid receptors.

(Modified from Wecker L: Brody’s human pharmacology, ed. 5. St. Louis, 2010, Mosby.)

Although tramadol is not chemically related to stronger opioid analgesics, it acts by weakly binding both µ- and δ-opioid receptors in the CNS. Tramadol may also interfere with serotonin and norepinephrine reuptake in descending inhibitory pathways.¹³ Tramadol is only partially affected by the opiate antagonist naloxone.³⁶

Indication

Short courses of opioid analgesics may be indicated for patients with moderate to severe CLBP who are unable to resume their activities of daily living and have failed to respond to other interventions. The severity of pain reported by patients is subjective, but can nevertheless be measured using simple instruments such as the visual analog scale (VAS) or numerical pain rating scale (NPRS), or more complex instruments such as the McGill pain questionnaire (MPQ) or Brief Pain Inventory (BPI). Repeated administration of these measures in patients with CLBP may be helpful in deciding whether or when opioid analgesics may be warranted if the severity of pain worsens or crosses a particular threshold established by the patient and clinician (Table 12-3).

TABLE 12-3 Indications for Opioid Analgesics

Source: www.drugs.com.

Additional instruments may also be helpful in identifying those patients with CLBP in whom opioid analgesics may be indicated. From a behavioral and psychological health perspective, it has been suggested that patients with chronic pain (including CLBP), can be divided into three categories: (1) adaptive coper, (2) dysfunctional, and (3) interpersonally distressed.³⁷ A questionnaire has been developed for use by pain management specialists to help make this determination. Of the three categories, only adaptive copers are likely to respond to longer courses of opioid analgesics. Adaptive copers typically demonstrate coherent symptoms, including pain that is consistent with the suspected underlying pathology, function that is concordant with their impairment, and mood that is appropriate to their levels of pain and function. Furthermore, adaptive copers have no history of addictive disease, and reasonable goals and expectations about the proposed intervention.

Patients who are categorized as being dysfunctional or interpersonally distressed should not be prescribed opioid analgesics. As a group, they tend to respond poorly to all biomedical interventions aimed at specific anatomic structures or pathways. Their pain and function often appear out of proportion to the suspected pathology and each other. These patients may also have psychological comorbidities, including depression, character disorder, or a prior history of addiction. Anecdotally, such patients with CLBP may also have a history of consulting with numerous physicians, can appear overly demanding, and request several inappropriate interventions or diagnostic tests.

Assessment

Before receiving opioid analgesics, patients should first be assessed for LBP using an evidence-based and goal-oriented approach focused on the patient history and neurologic examination, as discussed in Chapter 3. Prescribing physicians should also inquire about medication history to note prior hypersensitivity or allergy, or adverse events with similar drugs, and evaluate contraindications for these types of drugs. Clinicians may also wish to order a psychological evaluation if they are concerned about the potential for medication misuse or potential for addiction in certain patients. Diagnostic imaging or other forms of advanced testing is generally not required prior to administering opioid analgesics for CLBP.

Clinical Practice Guidelines

Five of the recent national CPGs on the management of CLBP have assessed and summarized the evidence to make specific recommendations about the efficacy of various opioid analgesics.

Systematic Reviews

Cochrane Collaboration

An SR was conducted in 2006 by the Cochrane Collaboration on opioids for CLBP.⁴⁴ A total of four RCTs were included, three comparing tramadol to placebo, and one comparing opioids to naproxen.^24,31–33

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