Pharmacologic management of chronic pain.

Chronic pain is a multifactorial condition with both physical and psychological symptoms, and it affects around 20% of the population in the developed world. In spite of outstanding advances in pain management over the past decades, chronic pain remains a significant problem. This article provides a mechanism- and evidence-based approach to improve the outcome for pharmacologic management of chronic pain. The usual approach to treat mild to moderate pain is to start with a nonopioid analgesic. If this is inadequate, and if there is an element of sleep deprivation, then it is reasonable to add an antidepressant with analgesic qualities. If there is a component of neuropathic pain or fibromyalgia, then a trial with one of the gabapentinoids is appropriate. If these steps are inadequate, then an opioid analgesic may be added. For moderate to severe pain, one would initiate an earlier trial of a long term opioid. Skeletal muscle relaxants and topicals may also be appropriate as single agents or in combination. Meanwhile, the steps of pharmacologic treatments for neuropathic pain include (1) certain antidepressants (tricyclic antidepressants, serotonin and norepinephrine reuptake inhibitors), calcium channel alpha(2)-delta ligands (gabapentin and pregabalin) and topical lidocaine, (2) opioid analgesics and tramadol (for first-line use in selected clinical circumstances) and (3) certain other antidepressant and antiepileptic medications (topical capsaicin, mexiletine, and N-methyl-d-aspartate receptor antagonists). It is essential to have a thorough understanding about the different pain mechanisms of chronic pain and evidence-based multi-mechanistic treatment. It is also essential to increase the individualization of treatment.

INTRODUCTION

Chronic pain is one of the most prevalent, costly, and disabling conditions in both clinical practice and the workplace, yet it often remains inadequately treated [1]. The available guidelines are not universally accepted by those involved in pain management, and pain treatment seems to be mainly guided by tradition and personal experience [2]. Moreover, chronic pain commonly coincides with depression and sleep disturbance, as well as mood and anxiety disorders.

Neuropathic pain has recently been defined as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system" [3]. Treatment of neuropathic pain is challenging. Compared to patients with nonneuropathic chronic pain, patients with neuropathic pain seem to have higher than average pain scores and a lower health-related quality of life (even after adjusting for pain scores); they require more medication and they report less pain relief with treatment [4,5].

Therefore, it is not so easy to plan effective pharmacologic therapy for chronic pain. In this article, we will discuss the major classes of medications as they relate to chronic pain management and we offer better treatment decisions and combination therapy by increasing physicians' knowledge of the pharmacological options that are available to manage different pain mechanisms.

SPECIFIC MEDICATIONS

1. Nonopioid analgesics

Aspirin and other related compounds constitute a class of drugs known as nonsteroidal anti-inflammatory drugs (NSAIDs). NSAIDs have 3 desirable pharmacological effects: anti-inflammatory, analgesic, and antipyretic effects. All NSAIDs and COX-2 agents appear to be equally effective in the treatment of pain disorders [6]. While gastrointestinal (GI) adverse effects have traditionally been considered the most common and worrisome complication of NSAIDs, the cardiovascular risk has gained increasing attention, and this has prompted the American Heart Association to recommend acetaminophen, nonacetylated salicylates and even short-term opioids instead of NSAIDs and particularly COX-2 agents in patients with coronary artery disease [7]. Acetaminophen has analgesic and anti-pyretic effects similar to NSAIDs, but it lacks a specific anti-inflammatory effect. Acetaminophen is a slightly weaker analgesic than NSAIDs [8-10], but it is a reasonable first-line option because of its more favorable safety profile and low cost. However, acetaminophen is associated with asymptomatic elevations of aminotransferase levels at dosages of 4 g/day even in healthy adults, although the clinical significance of these findings is uncertain [11].

2. Tramadol

Although the mode of action of tramadol is not completely understood, tramadol is a drug with a dual activity: one-third of its activity is due to an opioid-like mechanism and two-thirds are due to a mechanism similar to amitriptyline. It truly represents a multimodal drug to consider for pain management strategies [12]. Tramadol has proven effective to treat osteoarthritis (OA), fibromyalgia (FM), and neuropathic pain (NP). Because tramadol is an unscheduled drug, clinicians may not be aware of its opioid effect. However, it should be used with some caution in persons recovering from substance use disorders. While the degree of physical dependence appears to be relatively mild, patients have reported symptoms of psychic dependence, such as craving tramadol when discontinuing the drug [13]. Seizures have been reported with tramadol use in the form of serotonin syndrome. Therefore, patients with a history of seizures and those taking a tricyclic or SSRI antidepressant, a monoamine oxidase inhibitor, an antipsychotic drug, or other opioids may be at an increased risk for seizures [14]. Daily doses of tramadol should not exceed 400 mg.

3. Opioid analgesics

Most available opioids are µ-opioid receptor agonists or drugs with direct affinity for µ-opioid receptors. The pure agonists have no apparent ceiling effect for analgesia. The exception is meperidine (Demerol®) that is limited by an active metabolite nor-meperidine, which is associated with excitatory side effects with a risk of seizures. Meperidine is not recommended for the treatment of chronic pain. Partial agonists with mixed agonist-antagonist action are generally not indicated for the treatment of chronic pain [15].

There is growing evidence that controlled-release opioid analgesics have a role to play in patients with chronic pain. A recent meta-analysis of 41 randomized controlled trials involving 6,019 patients found that opioids were more effective than placebo for both the pain and functional outcomes of patients with nociceptive and neuropathic pain [16]. The guidelines for the use of opioid analgesics for chronic noncancer pain have been established by the Canadian Pain Society [17], and the evidence supports the assertion that opioids are a reasonable and efficacious treatment for people with chronic pain [18]. The average duration of the trials was only 5 weeks (range: 1-16 weeks) and so there is a need for longer-term trials for examining the efficacy and safety parameters. The recommended front-line agents include hydromorphone, morphine, and oxycodone used orally on a time-contingent basis. Additional options include the fentanyl patch for cases where the oral route is not a reasonable option (malabsorption, vomiting) or it has failed, and methadone if the previous conventional opioids have failed [19]. An evidence-based review evaluated the long-acting opioids and short-acting opioids for chronic noncancer pain [20]. The author concluded that there is insufficient evidence to suggest that 1 long-acting opioid is superior to the others.

A systematic review of 34 trials with 4,212 patients provided information on the adverse events related to opioid use for treating noncancer pain [21]. Only 3 side effects (nausea, constipation, and somnolence) occurred significantly more frequently with opioids at 14%, 9%, and 6%, respectively, than with placebo. A considerable proportion of patients on opioids (22%) withdrew because of adverse events. Because most of the trials were short (< 4 weeks) and the authors did not titrate the dose, the implications of opioids for long-term use in clinical practice are less certain. Eisenberg et al. [22] also reported adverse events in their systematic review of opioids for NP. Opioid therapy compared to placebo resulted in higher reports of nausea (33% vs. 9%), constipation (33% vs. 10%), drowsiness (29% vs. 12%), dizziness (21% vs. 6%), and vomiting (15% vs. 3%). More patients on opioids withdrew because of adverse effects (11% vs. 4%). Endocrinological abnormalities, such as hypogonadism and erectile dysfunction, may be associated with long term use of opioid therapy [23,24]. In women, opioid use has been associated with amenorrhea and decreased levels of sex hormones [25]. Opioid treatment may be associated with impaired neuropsychological performance regarding reaction times, psychomotor speed, and working memory [26]. However, a recent systematic review concluded that stable doses of opioids did not impair driving performance [27].

1) Maximize the nonopioid analgesic strategies first (i.e., a "delayed" opioid approach).

2) Inform subjects of the risks, including addiction, before initiating opioid therapy.

3) Facilitate the use of opioid agreements (contracts) for patients initiating opioid therapy or those with increasing doses of opioids. The key points include specifying the frequency of obtaining medications, providing timely refills but no early replacement for lost or stolen prescriptions, providing safe storage, no sharing, single-source prescribing, monitoring through urine screens, and adhering to monitored visits.

4) Schedule follow-up visits at 2- to 3-month intervals and perform periodic urine testing to confirm adherence.

5) Monitor the pain severity and pain-related functional impairment at follow-up visits since the analgesic response may wane in some patients over time.

6) Avoid opioid dose escalations without first assessing the pain severity and the pain's interference with daily life.

7) View opioid initiation as an empiric trial. Consider discontinuing opioids if they are not beneficial.

8) Consider opioid rotation according to the opioid conversion ratio (Table 1) if tolerance to 1 opioid is suspected.

Table 1

Oral and Transdermal Opioid Analgesic Equivalence

*Duration of analgesia is dose dependent; the higher the dose, usually the longer the duration. †These high doses of codeine and meperidine are not recommended clinically. ‡Equianalgesic data not available for hydrocodone. §In opioid-tolerant patients converted to methadone, start with 10-25% of equianalgesic dose. Also, the half-life of methadone can vary widely from 12 to 190 h.

9) If patient is a high-risk candidate for opioids (particularly those with a current or past SUD including alcohol or drugs), consider referral to a pain specialist.

4. Antidepressants

Patients often discontinue this type of medication because side effects occur early, while the analgesia may take several weeks to occur. They must be informed they will become tolerant to the side effect and that analgesia needs some weeks to be evident. Patients must be informed about the rationale for antidepressant therapy and that they are not being treated as though they are affected by psychological problems [28-30]. Antidepressants work at the spinal level by inhibiting the reuptake of the neural transmitters norepinephrine and serotonin, and so this potentiates the inhibitory pathway in the dorsal horn of the spinal cord and at the ectopic sites in the peripheral nerves by blocking Na channels.

1) Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs):

Tricyclic antidepressants have the longest track record of any antidepressant class for the treatment of multiple pain conditions. Typically, the doses of TCAs used in clinical trials for pain relief pain have been lower (e.g., 25-100 mg amitriptyline or equivalent) than the doses that are typically necessary for treating depression. However, some experts have found that titrating TCAs to higher doses (with an option of monitoring the serum levels) may further benefit a subset of patients. The advantages of TCAs include decades of clinical experience with TCAs for pain management and their low cost. The disadvantages of TCAs are side effects (which may be less when prescribing the lower doses used for analgesia), including cardiovascular effects (e.g., hypertension, postural hypotension, arrhythmias), falling down in older adult patients, and there is also potential lethality with an overdose.

TCAs are superior to SSRIs for pain management. Admittedly, the statistical comparisons that have been done are not as conclusive as direct comparisons of anti-depressants within the same trial. Another review concluded that SSRIs appeared to have a relatively weak effect for ameliorating chronic pain [31].

2) Serotonin-norepinephrine reuptake inhibitors (SNRIs):

Duloxetine has been proven superior to placebo in three 12-week randomized, placebo-controlled trials that enrolled patients with pain due to diabetic peripheral neuropathy [32-34]. Both the patients with and without depression were enrolled in the trials, although the path analysis estimated that more than 90% of the analgesic effect in the duloxetine-treated patients with diabetic neuropathy was attributable to a direct analgesic effect, with less than 10% possibly explained by an antidepressant effect [35]. Duloxetine is also FDA approved for treating the chronic widespread pain of FM [36-38]. A 6-week trial of extended-release venlafaxine in 224 patients with diabetic neuropathy found venlafaxine superior to placebo [39]. Venlafaxine may also be useful in other painful conditions [40], but it does not have the FDA approved indication for pain treatment.

A recent meta-analysis of 5 trials in depressed patients reported a very small and statistically insignificant analgesic effect for duloxetine [41]. Another meta-analysis of 8 trials that compared duloxetine with paroxetine or placebo for the painful physical symptoms of depression likewise concluded that there was insufficient evidence for an analgesic effect of duloxetine [42]. In all of these depression trials, pain was examined as a secondary outcome, and in all but 2 trials, an important proportion of patients had no pain. A subsequent placebo-controlled trial of duloxetine in patients with depression and moderate-to-severe pain, but no organic pain diagnosis, found a significant benefit from duloxetine for both pain and depression symptoms [43].

5. Anticonvulsants

Anticonvulsants have been used for the management of pain since the 1960s and along with antidepressants, they constitute 1 of the 2 most important adjunctive classes of medications for pain management. The clinical impression is that they are useful for chronic NP, especially when the pain is described as lancinating or burning. Gabapentin and pregabalin have the strongest evidence for the treatment of pain. These 2 "gabapentinoids" act as neuromodulators by selectively binding to the α2-δ-subunit protein of the calcium channels in various regions of the brain and the superficial dorsal horn of the spinal cord. They also have a peripheral analgesic action [44-46]. These actions result in inhibiting the release of excitatory neurotransmitters that are important in the production of pain.

In the 14 chronic NP trials, 42% of the participants improved (i.e., pain relief of 50% or greater) on gabapentin vs. 19% on placebo. The withdrawal rates were 14% for gabapentin vs. 10% for placebo. The FDA has approved pregabalin for the treatment of NP associated with diabetic peripheral neuropathy and PHN and for the treatment of FM.

Gabapentin and pregabalin should be considered as the first-line anticonvulsants for NP conditions other than trigeminal neuralgia. Gabapentin is now available in a generic formulation, making it less costly than pregabalin. Conversely, pregabalin has a simpler dosing schedule (twice daily compared to 3 to 4 times daily), possibly a simpler dose titration, and an additional FDA indication (FM).

Other drugs worth trying are lamotrigine, clonazepam, and valproate. Carbamazepine and Oxcarbazepine are considered the first effective drugs for trigeminal neuralgia. Carbamazepine and Oxcarbazepine act peripherally on Na channels while the others work at spinal levels by different mechanisms with a common inhibitory effect at the pre- and post-synaptic levels in the dorsal horn of the spinal cord [29,47].

6. Skeletal muscle relaxants

Most skeletal muscle relaxants are FDA approved for either spasticity (baclofen, dantrolene, and tizanidine) or musculoskeletal conditions (carisoprodol, chlorzoxazone, cyclobenzaprine, metaxalone, methocarbamol, and orphenadrine) [48]. The mechanism of action for the latter category of agents is unclear, but it may be related in part to sedative effects. Cyclobenzaprine is the best studied muscle relaxant in musculoskeletal disorders overall; in 21 fair-quality trials, it has consistently proven superior to placebo for FM as well as for pain relief, muscle spasms, and improving the functional status in other disorders. Muscle relaxants have a limited role for the treatment of chronic pain, except for cyclobenzaprine as 1 option for treating FM.

7. Topical analgesics

A potential advantage of topical agents is avoiding systemic side effects that are often associated with oral medications. The disadvantages are that only localized areas of pain can be effectively treated and that irritating skin reactions occur in a minority of patients. Topical analgesics probably have a circumscribed role in treating localized areas of mild to moderate neuropathic or osteoarthritic pain, either as an adjunct with other medications or as an alternative for patients who prefer not to ingest pills. Several topical analgesics (lidocaine, capsaicin, and salicylate) have been studied in multiple trials. A 5% lidocaine patch has an FDA indication for PHN. It is applied for 12 h daily. The systemic levels absorbed are very low due to lidocaine working via a local mechanism.

Capsaicin is an alkaloid derived from chili peppers; repeated application is thought to lead to depletion of substance P from the primary afferent neurons [49]. The main disadvantage of capsaicin is the initial burning sensation, which may persist for days. Capsaicin must be applied 3-4 times per day over the entire painful area for up to 6-8 weeks before optimal pain relief can be achieved. Capsaicin 0.075% is used for neuropathic pain, and Capsaicin 0.025% is used for arthritic pain. A new potent (8%) strength patch has shown promising results. It needs to be applied in the hospital after patient sedation or after the skin has been anaesthetized because it is strongly irritating, but a 1 h application can result in analgesia that lasts for several weeks. Mason et al. [50] recently reviewed the clinical trial evidence for capsaicin, including 6 trials for NP and 3 trials for musculoskeletal conditions. They found that 57% of the patients with NP achieved at least 50% pain relief with capsaicin, compared to 42% of the patients on placebo; for patients with musculoskeletal conditions, the response rates were 38% vs. 25%, respectively [50]. Around one third of the patients experienced local adverse events with capsaicin.

Topical salicylate has proven superior to placebo for treating chronic pain [51]. However, the larger, more rigorous trials have tended to be negative. A recent study suggests topical ibuprofen may also be beneficial for knee OA [52].

TREATMENT PLAN

First of all, it is important that physicians understand the multifactorial nature of chronic pain and the physiological differences between nociceptive pain and neuropathic pain. They had better do a multi-mechanistic approach with taking into account stepwise selection of pharmacotherapy (Fig. 1) [15]. A multi-mechanistic approach means combining 2 substances from different drug classes, or administering an analgesic with 2 different mechanisms of action. In some circumstances, a single compound capable of addressing both nociceptive and neuropathic pain is desirable [2].

Fig. 1

Treatment algorithm for pharmacotherapy of chronic noncancer pain. In general, if one agent in a class of medications does not provide adequate analgesia or causes limiting side effects, it is worth pursuing serial trials of 1 or 2 others from the class. Topicals may be introduced at any point as a sole agent or in combination.

In addition, physicians have to modify treatment for pediatric, geriatric, hepatic, and renal failure patients. Generally, all drugs should be administered cautiously for these cases. The dose should be low and titrated slowly to avoid toxicity. It has been suggested that up to 40% of children lack the enzyme to metabolize codeine to morphine [53]. In these circumstances, a medication substitution should be attempted. Meperidine use is not recommended in children because of the side effects encountered due to the main metabolite, normeperidine [54]. Although NSAIDs are a good option, they should be avoided in children younger than 6 months of age and children with NSAID or aspirin allergy, hypovolemia or dehydration, renal or hepatic failure, peptic ulcer disease, or coagulopathies [54]. Children on anticoagulants, steroids, and nephrotoxic agents should not receive NSAIDs.

The considerations for geriatric patients are as follows. First, consider the risk/benefit ratio of NSAIDs. Second, when using NSAIDs in persons 60 years and older, a proton pump inhibitor should be added as prophylaxis against GI bleeding in those patients with GI symptoms (dyspepsia or gastroesophageal reflux) or those patients who are on antiplatelet agents (e.g., aspirin, clopidogrel) or corticosteroids [55]. Third, amitriptyline and cyclobenzaprine should probably be avoided due to their highly anticholingergic properties. Fourth, opioids should be started at low doses and titrated slowly, and special attention should be paid to preventing constipation.

Aspirin should be avoided for patients with end-stage renal disease, and dosage adjustments should be made when ASA is used for long-term therapy in a hepatically compromised patient [56]. Acetaminophen is used with an increased dose interval in hepatic and renal failure patients [57,58]. Tramadol, hydromorphone, and morphine are used very cautiously at a reduced dose in the presence of kidney and liver abnormalities [56,59,60]. Few studies are available to examine the safety of morphine in conjunction with liver failure; any hepatic recommendations are not available. Codeine, dihydrocodeine, and dextropropoxyphene are not recommended for use in the presence of renal failure [59,60]. Fentanyl is an ideal choice for patients with renal failure because of the lack of active metabolites, yet it is likely that fentanyl clearance is delayed because of hepatic failure, and this is because fentanyl is subject to a high hepatic extraction ratio [61].

Three evidence-based consensus guidelines for the pharmacologic treatment of neuropathic pain have recently been updated: (1) the International Association for the Study of Pain Neuropathic Pain Special Interest Group (NeuPSIG) guidelines, (2) the Canadian Pain Society (CPS) guidelines, and (3) the European Federation of Neurological Societies (EFNS) guidelines (Table 2) [62]. These guidelines all recommend TCAs, gabapentin, and pregabalin as first-line treatment options for patients with neuropathic pain (excluding trigeminal neuralgia). They also recommend reserving opioid analgesics and tramadol as second- or third-line options in most cases, despite the evidence of their efficacy for neuropathic pain. In 2 of the guidelines, topical lidocaine is recommended as a first-line treatment for patients with localized peripheral neuropathic pain (particularly in patients with postherpetic neuralgia and allodynia), whereas the other guideline considers topical lidocaine a second-line treatment. The NeuPSIG guidelines recommend duloxetine and venlafaxine as first-line treatment options, but the Canadian Pain Society and EFNS guidelines recommend these SNRIs as second-line options for patients with painful polyneuropathies.

Table 2

Comparison of Neuropathic Pain Treatment Guidelines, Excluding Trigeminal Neuralgia*

NeuPSIG: Neuropathic Pain Special Interest Group, CPS: Canadian Pain Society, EFNS: European Federation of Neurological Societies, PPN: painful polyneuropathy, PHN: postherpetic neuralgia, CP: central pain, SNRIs: serotonin and norepinephrine reuptake inhibitors, NP: neuropathic pain. *Only medications considered first or second line in 1 of the guidelines are presented. †Opioid analgesics and tramadol were considered first-line options in the following circumstances: for the treatment of acute NP, episodic exacerbations of severe NP, neuropathic cancer pain, and during titration of a first-line medication in patients with substantial pain.

Even if a correct treatment is started, there are some concerns to keep in mind. Insufficient dosage is another possible explanation for treatment failure. It may be difficult to maintain the balance between adequate pain relief and acceptable tolerability, as well as side effects, of the pharmacotherapy. This may be explained by the hypothesis of the Vicious Circle, which is particularly applicable to classical opioids, but also plays a role in combination therapy (Fig. 2) [2]. Informing and supplying the patient with information is mandatory not only at the beginning, but also when the effective drug combination and dosages have been found. The patient should be convinced that chronic pain needs chronic therapy. Patients frequently stop therapy due to fear of addiction and toxicity. Also, the cost of the therapy is another reason to stop the treatment. Finally, it is necessary that physicians individualize the pharmacotherapy of each patient.

Fig. 2

The Vicious Circle showing interaction of influencing factors.

SUMMARY

A number of medications have proven to be effective in chronic pain disorders and their use individually or in combination should improve the management of chronic pain. Especially for neuropathic pain, the medications recommended as first-line treatments include TCAs, SNRIs, calcium channel α2-δ ligands, and lidocaine patch. Opioid analgesics and tramadol are recommended as second-line treatments that can be considered for first-line use in selected clinical circumstances. A thorough understanding of pain mechanisms and good communication between physicians and patients are required to improve patient outcomes. Avoiding ineffective treatments and maximizing the treatments that have been proven beneficial in clinical trials (i.e., evidence-based treatments) are likely to produce better outcomes than have often been experienced by clinicians and patients in the management of chronic pain. Additionally, identifying and co-managing pain that is comorbid with psychiatric disorders have promise for improving both the physical and psychological outcomes. Furthermore, the multi-modality treatment of chronic pain incorporates not only this approach to pharmacological treatment, but also non-pharmacological strategies such as interventional pain management, physiotherapy, psychotherapy, and pain rehabilitation.