Difficult-to-treat chronic pain syndromes

Pain is one of the most common reasons patients seek medical care, so it is inevitable that primary-care clinicians will be dealing with  difficult-to-treat pain syndromes. Some of these syndromes include low back pain (LBP); fibromyalgia; and such neuropathic conditions as postherpetic neuralgia, diabetic neuropathy, complex regional pain syndrome (CRPS), and oncology-related syndromes (e.g., postmastectomy pain). Effective treatment of chronic pain requires a multimodal approach that includes pain medication, adjunct medications, and other forms of therapy (e.g., exercise and relaxation).

The impact of chronic pain

Pain that lasts beyond the normal healing period or longer than three to six months is considered chronic. It can be persistent or appear periodically. Some patients have more pain during the day, while others experience higher levels at night. No matter what the cause or pattern of the pain, its chronicity causes physiologic and psychological stress that wears on the patient physically and emotionally.  

Chronic pain also takes a toll on public health, robbing communities of productive work time, billions of dollars, and most important, overall quality of life. It can affect anyone and can lead to depression, sleep disturbances, and anxiety. Clinicians who treat pain need a comprehensive long-term plan to return their patients to a reasonable level of functionality. Such treatment requires skill at pain assessment as well as medication selection and titration. The clinician must also incorporate nonpharmacologic therapies and provide adequate patient education.

Older patients can have special needs related to pain management and may experience many of the difficult-to-treat pain syndromes. An estimated 80% of patients in long-term-care facilities experience chronic daily pain, and 25%-50% of community-dwelling elders have chronic daily pain that impacts their ability to function.¹ Many older patients do not like to take pain medications because of side effects (e.g., constipation, mental confusion). This creates a situation in which pain is present but the means to control it are viewed as unacceptable. The high incidence of chronic pain in the older patient and the limited ability to manage it makes effective treatment difficult.

Assessing pain

When pain is the primary complaint, an integral part of the history and physical is a comprehensive assessment that includes intensity, location, duration, quality, alleviating and aggravating factors, and functionality. For acute pain, a simple numeric rating in which 0 equals no pain and 10 is the worst possible pain is sufficient. For chronic pain, however, a multidimensional assessment tool is a better option to obtain all salient information.

Several tools for assessing chronic pain are commonly used, such as the Brief Pain Inventory and the McGill Pain Questionnaire, but the Brief Pain Impact Questionnaire (BPIQ) (see sidebar) is much easier to use clinically and provides a template for the patient interview. Using the BPIQ to structure the patient interview around the pertinent questions on functionality, ability for self-care, exercise, sleep, depression, and pain medication provides a baseline for comparison during future appointments.

Choosing the appropriate medication

The physical exam should be focused on the complaint of pain as well. A thorough neurologic assessment is key, and palpating painful areas can help detect any radiation or radicular aspects of the pain. A simple test for LBP is the straight-leg raise. Using von Frey's filaments to determine sensitivity is helpful in locating and detecting the spread of neuropathic pain.

Once the history and physical are complete, choosing the appropriate intervention is crucial. Many clinicians are reluctant to start opioid medications. Fear of federal drug enforcement oversight and addiction can drive prescribers away from opioids. Lack of knowledge on how to dose and combine opioids can also limit their use. Oftentimes clinicians opt to begin treatment with acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) instead. Depending on the source and intensity of the pain, this may lead to undertreatment, which could exacerbate the problem.

Which opioid medication?

Although some opioids are natural and others are synthetic, they all bind to the µ-opioid receptors in the spinal cord and periphery to produce analgesia. There are other differences as well. Some opioids have shorter action potentials (e.g., fentanyl) and others have extremely long half-lives (e.g., methadone). In addition, there are combination drugs with shorter duration and limited maximum doses related to the use of acetaminophen (e.g., oxycodone/acetaminophen and hydrocodone/acetaminophen).

An analgesic ladder endorsed by the World Health Organization (WHO) (Figure 1) can be a helpful guide.² The three steps of the ladder list medications that are appropriate for mild, moderate, and severe pain.

When to use an extended-release medication

For a patient with chronic pain, an opioid medication with extended-release action may be the best choice. When the patient is consistently using a short-acting medication (e.g., oxycodone/acetaminophen), has consistent daily pain that needs better relief, and has reached the maximum daily dose of acetaminophen, it is time to move to an extended-release medication. There are several options, including extended-release morphine, oxycodone, or tramadol (Ultram).

One medication often prescribed by pain specialists looking for a less expensive alternative to extended-release medications is methadone. This agent, which is commonly used in maintenance programs for heroin addicts, is also a very powerful pain reliever. It can be prescribed only by clinicians holding a Drug Enforcement Agency license and requires very careful consideration prior to use.

Methadone is very difficult to titrate. With pain relief lasting only six hours and a half-life as long as 150 hours, the possibility of oversedation and respiratory depression is substantial. Dosing should start in the lower range of 2.5-5 mg and can be increased every six days. Careful monitoring for side effects is essential. Additionally, there is the potential for the cardiac arrhythmia, torsades de pointes. All patients on methadone therapy should have a baseline ECG and repeat testing every six months to monitor for cardiac complications. Methadone should be prescribed for pain control only by practitioners who are aware of the potential pitfalls and understand the mechanism and action of the drug.

Avoiding addiction

All patients who use opioids to control daily pain will become dependent on the medication. Dependency is defined as a condition in which sudden stoppage of the medication causes symptoms of withdrawal. Addiction, on the other hand, is characterized by the presence of the four Cs: (1) lack of Control, (2) Craving for the drug of choice, (3) Compulsive use, and (4) Continued use despite harm.³ Dependency and addiction are not the same and should not be confused.

Although there is a risk of addiction when long-term opioids are used, it is not as high as many practitioners assume. In a study of 810 primary-care patients on long-term opioids for chronic pain, the incidence of addiction was 3.8%.⁴

Several techniques can be used to minimize concerns with prescribing long-term opioids. Both the Opioid Risk Tool (ORT) and the Screener and Opioid Assessment for Patient with Pain-Revised (SOAPP-R) are good screening instruments. Each screening tool is a set of questions that can help determine if the patient will demonstrate aberrant drug-taking behaviors (ORT)⁵ (Table 1) or if they have a high risk for addiction with opioids (SOAPP-R).

Providing the patient with an opioid agreement that lists the clinic rules for prescribing long-term opioids, defines addiction/dependency/tolerance, and outlines the drug's dose and side effects can lessen the burden for the prescriber. By signing the agreement, the patient consents to random urine drug screens. The consequences of a positive screen for nonprescribed opioids, illicit substances, or other drugs of abuse (e.g., benzodiazepines) are also included in the agreement.

As always, these tools should be used in conjunction with each other to provide a more comprehensive picture of the patient and his treatment.

Applying the principles

The proper use of available medications can benefit patients with a number of difficult-to-treat pain syndomes.

Low back pain This is one of the most common pain complaints primary-care practitioners confront. A recent study found that two thirds of adults will suffer from low back pain at some time.⁶ An estimated 95% of Americans will have degenerative disk disease by age 50.⁷

LBP can be divided into two categories; acute (resolves within 6-12 weeks no matter what therapies are used) and chronic (pain does not improve within 12 weeks).

The American College of Physicians (ACP) in conjunction with the American Pain Society (APS) have developed a joint guideline that outlines the best evidence-based recommendations for treating patients with LBP.⁸ The first recommendation is that clinicians perform a focused history and physical to place the patient into one of three categories: (1) nonspecific LBP (e.g., musculoskeletal strain); (2) back pain potentially associated with radiculopathy or spinal stenosis; or (3) back pain potentially associated with another spinal cause (e.g., compression fracture, tumors). The guideline also recommends assessing psychosocial factors and emotional distress, which can be strong indicators of treatment outcome.

With regard to imaging, the ACP/APS panel advises against routine use. Instead, imaging for patients with nonspecific LBP can be deferred. Prompt MRI (preferred) or CT is recommended for patients who have severe or progressive neurologic deficits or when serious underlying conditions are suspected and delay in treatment would be detrimental. In cases of persistent LBP with or without radiculopathy or suspected spinal stenosis, MRI (again preferred) or CT should be done only if the patient is a candidate for surgery or epidural steroid injection. Imaging preferences are based on a desire to reduce patient exposure to radiation, control treatment costs, and avoid less optimal outcomes with other choices.⁸

Once the patient is diagnosed, a treatment option must be chosen. As previously discussed, fear of addiction affects the treatment decisions of many clinicians, but most LBP patients expect to leave their clinician's office with a prescription. In one study, 80% of primary-care patients who saw their provider for LBP were prescribed at least one medication at their initial office visit, and more than one third were prescribed two or more drugs.⁹

The ACP/APS guideline recommends acetaminophen and NSAIDs as first-line medication, with opioids and tramadol reserved for patients who have severe and disabling pain.⁸ While the risk and long-term effects associated with short-term opioid use are fairly well recognized, the effects of long-term use are less clear.¹⁰ Recently, long-term use of opioids for chronic pain has been linked to opioid hyperalgesia, an atypical increase in pain severity unrelated to the original pain stimulus.¹¹  

Other medications to consider for LBP include muscle relaxants, tricyclic antidepressants, antiseizure medications (especially gabapentin [Neurontin]), and benzodiazepines. Of course, these medications are not benign and have side effects that some patients will find intolerable. Benzodiazepines have the potential for abuse. Systemic steroids are not indicated. Some herbal remedies (e.g., devil's claw, capsaicin) have been found to have limited benefits.⁹

Nonpharmacologic recommendations for acute LBP include spinal manipulation, superficial heat, exercise therapy, interdisciplinary rehabilitation, and cognitive behavior therapy.⁸ For chronic LBP, the ACP/APS guideline recommends acupuncture, exercise therapy, massage therapy, viniyoga-style yoga, progressive relaxation, spinal manipulation, and interdisciplinary rehabilitation.⁸ There is conflicting evidence with regard to the efficacy of epidural steroid injections for LBP, and prolotherapy has been found to be effective for pain relief only when combined with a structured physical-therapy regimen.¹²

Fibromyalgia A diagnosis of exclusion, fibromyalgia occurs in 2%-5% of the population (mostly women).¹³ No common laboratory tests are confirmatory, so the patient report is the basis for diagnosis. Substance P, a pain-facilitating agent, is found at levels three to five times normal in the cerebrospinal fluid of fibromyalgia patients. Nerve growth factor, which can affect sensory processing, is also elevated in these patients.¹⁴ Deficits in serotonin, norepinephrine, and dopamine have also been found. These deficits are thought to account for some of the depressive symptoms associated with fibromyalgia.

Treatment of fibromyalgia is made difficult by the range of symptoms, e.g., painful tender points on the body, sleep disturbance, fatigue, mood disturbances, cognitive loss, restless legs, temporomandibular joint pain, irritable bowel/bladder, anxiety, depression, and panic attacks.¹³ Recommended treatment options include amitriptyline, cyclobenzaprine, cardiovascular exercise, cognitive behavior therapy, patient education, and multidisciplinary therapy. Opioids are not recommended for long-term treatment. Recently, both pregabalin (Lyrica) and duloxetine (Cymbalta) have been approved by the FDA for treating fibromylagia.

Neuropathic pain The International Association for the Study of Pain defines neuropathic pain as pain initiated or caused by a primary lesion or dysfunction in the nervous system (peripheral or central) that disrupts impulse transmission and modulation of sensory input.¹⁵ More simply, neuropathic pain is pain that has no stopping mechanism and can be self-generating once the stimulus is established.

Neuropathic pain is also caused and sustained by an inflammatory response. Once initiated, the human body responds by activating pain facilitators (e.g., bradykinin, substance P, hydrogen ions, interleukin-1beta, nerve growth factor, prostaglandins, histamine, adenosine triphosphate, and tumor necrosis factor).¹⁶ When this heightened inflammatory response is triggered, primary and secondary sodium channels are activated, causing neuronal hyperexcitability that is connected to pain production.

The words and phrases used to describe the pain and its presentation can indicate neuropathic pain. Such terms as “burning,” “painful tingling,” “pins and needles,” “strange sensations,” “shooting,” or “feels like electricity” point to some type of nerve damage. Patients may also complain of cold sensitivity. There can be swelling, hair loss, and skin changes in the affected area. Touch or movement may set off abnormally high levels of pain.

Treatment recommendations for neuropathic pain do not include opioids as a first-line option unless pain is severe. Instead, try the following: tricyclic antidepressants (e.g., amitriptyline, nortriptyline, desipramine); selective serotonin and norepinephrine reuptake inhibitors (e.g., duloxetine, venlafaxine)¹⁷; calcium channel alpha₂; ligand drugs (e.g., gabapentin, pregabalin)¹⁸; and targeted topical analgesics (e.g., 5% lidocaine patch) used alone or in combination with other medications.¹⁹

Opioids are considered second-line medications that should be used when needed for pain flares, cancer-related pain, or at initial onset if pain is severe.²⁰

Such nonpharmacologic therapies as relaxation, cognitive behavior therapy, and interventional options may also be helpful.

Neuropathic pain syndromes with specific treatment options include three involving the peripheral nervous system (postherpetic neuralgia, postmastectomy syndrome, and diabetic neuralgia) and CRPS types I and II, which affect the central nervous system.

•    Postherpetic neuralgia occurs most commonly in patients older than age 50 who have shingles, the reactivation of the varicella-zoster virus that is present on peripheral neurons. These neurons become hypersensitive to touch, and the pain is severe. The distribution of the rash is quite distinctive, as
it is found only in the dermatomal distribution of the affected neuron.

•    Postmastectomy pain syndrome develops in approximately 20% of women who undergo lumpectomy or mastectomy with node dissection. The syndrome is more common in younger women and those who are overweight. Patients will likely complain of the typical burning pain in the axilla and chest on the affected side, but they may also complain of “strange painful sensations” or “painful pins and needles.” ²¹ The pain is sustained by continued inflammatory response in the surgical area. Without early intervention, patients may be unable to fully rehabilitate the surgical-side arm. To avoid functional limitations, targeted topical analgesics, a neuropathic pain medication (e.g., gabapentin), and a short course of opioids will help manage the pain well enough to allow participation in physical therapy.

•    Painful diabetic neuropathy occurs in 37%-45% of type 2 diabetes patients and 54%-59% of type 1 patients.¹⁷ Sufferers report allodynia (perception of pain caused by normally nonpainful stimulus) as well as sharp, stabbing, burning pain coupled with numbness (most commonly in the feet). Treatment options include the targeted topical analgesics18 as well as the recommended oral medication regimen from the neuropathic pain guideline.²⁰

•    CRPS type I is a centrally mediated pain syndrome (formerly known as reflex sympathetic dystrophy) with no obvious nerve lesion. In contrast, type II has a detectable nerve lesion. CRPS can develop after surgery, a crush injury, or undertreated acute pain. Transmission moves from peripheral pain stimulus-response to a centrally mediated response that is not governed by the continued peripheral pain input, which makes the syndrome difficult to treat. The syndrome is characterized by sensitivity to heat/cold, hyperalgesia, abnormal swelling, muscle contractures, and high levels of pain for extended periods of time. Treatment can involve a multidisciplinary approach using neuropathic pain medications, physical therapy, and such interventional options as localized blocks.

Important considerations

When faced with especially challenging chronic pain conditions, a comprehensive assessment and a pain-focused history and physical provide important information about the cause of the pain. The descriptors patients use when reporting the pain can help determine whether it is musculoskeletal or neuropathic.
Choosing the right medication is essential for maximizing your chances at success with these more difficult-to-treat syndromes. National guidelines provide evidence-based recommendations.¹⁹ The WHO analgesic ladder can help determine which level of medication is the right fit for the patient's complaint. It is always wise to consider an extended-release opioid preparation if the patient is taking a number of short-acting opioids daily for consistent pain. Remember that the vast majority of patients on long-term opioids do not become addicted to their medications but are dependent on them to control their pain.

Ms. D'Arcy is a pain management and palliative-care nurse practitioner at Suburban Hospital in Bethesda, Md.

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All electronic documents accessed November 9, 2008.