Chronic pain management strategies

Introduction

Chronic pain is typically treated with a combination of medication and nonmedication therapies. While patients often initially want to focus treatment around medications, inclusion of nonmedication therapies generally offers the best long-term benefit. A large population survey found that 45% of patients reported their pain medications were very effective and an additional 41% felt their prescriptions were somewhat effective¹. Although medications were often helpful, 64% noted that at times their medications were not adequate to control their pain. These data suggest that, while medications are an important component of pain management, medications should be used in a comprehensive treatment programme, including additional nonmedication therapies to maximize treatment outcome.

Table 2.1 Pain medications

•	Simple, nonopioid analgesics
–	Acetaminophen/paracetamol
–	Nonsteroidal anti-inflammatory drugs
•	Adjuvant analgesics
–	Antidepressants
–	Neurostabilizing antiepileptics
–	Antispasmodics
–	Alpha-2 agonists
–	Topical agents (lidocaine, capsaicin)
•	Opioid analgesics
–	Immediate-release
–	Extended-release

Medication therapies

Pain medications include a wide assortment of therapies (Table 2.1). While simple and opioid analgesics were designed to reduce pain severity, other medications developed to treat alternative medical conditions may also offer analgesic properties, including medications designed to reduce mood disturbance, epilepsy, and elevated blood pressure. The majority of people with chronic pain use prescription medications, especially analgesics (2.1)¹.
Adjuvant therapies are most commonly used to treat neuropathic pain and chronic headache.

2.1 Common prescription medications for chronic pain. Among people with moderate or severe chronic pain in Europe and Israel, 53% reported currently using a prescription medication for pain. The most commonly used medication group was nonsteroidal anti-inflammatory drugs (NSAIDs). Some of the reported medications would be used for specific pain conditions, like beta- and calcium channel blockers or triptans for chronic headache and disease-modifying antirheumatic drugs (DMARDs) for rheumatoid arthritis. (Based on Breivik H, et al., 2006¹.)

A large, systematic review of outpatient chronic pain management analysed data from the existing literature to identify the number of patients needed to be treated to achieve an effective response from an assortment of medication therapies (Table 2.2)². None of these individual therapies was effective for most patients. These data show that a variety of therapies may be effective for chronic pain, but the individual patient will probably need to try several therapies before finding one that works well for him or her.

Mechanism of action of pain medications

Analgesics and adjuvant therapies influence both peripheral and central pain mechanisms (2.2, Table 2.3). Acute injuries result in an abnormal accumulation of sodium channels in affected nerves, leading to increased nerve firing and reduced threshold for depolarization. This sensitization of peripheral nerves enhances pain signalling. Once peripheral nerves are activated, changes in neuronal calcium levels and upregulation of NMDA receptors increase excitability of spinal neurons, resulting in central sensitization of pain pathways. Pain medications work by reducing peripheral or central sensitization or enhancing activity of descending inhibitory pathways from the brain. Serotonergic pathways from the periaqueductal gray and
noradrenergic pathways from the locus ceruleus dampen pain transmission by inhibiting pain pathways in the spinal cord, through interactions on inhibitory interneurons.

Table 2.2 Number-needed-to-treat (NNT) for efficacy of pain medications

Medication		NNT
Minor analgesics
	Acetaminophen/paracetamol	2.9
	Ibuprofen	2.0
	Tramadol	8.2
	Propoxyphene	7.5
Topical NSAIDs		3.0
Topical capsaicin		3.9
Antidepressants		3.0
Antiepileptics		2.5
Treatment efficacy was determined by a literature review of randomized, controlled clinical trials. NNT was defined as the number of patients needed to be treated to result in 1 patient with moderate-severe pain achieving >50% pain relief compared with placebo. NNT values between 2 and 4 were considered to indicate effective treatment. (Based on McQuay HJ, et al., 1997².)

Table 2.3 Mechanisms of pain medications

Pain function	Neural mechanism	Medications
Peripheral sensitization	Sodium channels	Antiepileptics (carbamazepine, oxcarbazepine, phenytoin, topiramate)
		Local anesthestics
		Tricyclic antidepressants
Central sensitization	Intracellular calcium	Antiepileptics (gabapentin, oxcarbazepine)
	NMDA receptor	Ketamine
		Dextromethorphan
Descending inhibition	Serotonin receptors	Antidepressants (tricyclics, SSRIs, SNRIs)
	Norepinephrine receptors	Tramadol
	Opioid receptors	Opioids
NMDA: N-methyl-D-aspartate; SNRI: serotonin and norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor

2.2 Mechanism of common analgesics. Myelinated A-δ fibres and unmyelinated C-fibres preferentially respond to noxious stimuli, sending impulses to the dorsal horn, where they synapse in outer laminae before crossing to ascend in the spinothalamic tract (A). Signals from the spinothalamic tract terminate in the thalamus, resulting in activation of the somatosensory cortex and limbic systems. Analgesics reduce pain transmission by influencing peripheral pain transduction and transmission or modulating central mechanisms in the brain or spinal cord (B).

Gender and ethnic influences on medication efficacy

Women are more sensitive to pain than men (2.3)³. Furthermore, analgesic response varies by gender. Although men experience a greater early effect from opioids, the overall analgesic response is greater and more persistent in women (2.4)⁴. Nonsteroidal anti-inflammatory analgesia, alternatively, is superior in men³. Gender differences in pain perception and treatment response may be at least partially explained by the important role of estrogen as a pain modulator.

Pain sensitivity and treatment effectiveness are also influenced by ethnicity. Although pain threshold is similar among ethnic groups, studies consistently show a lower pain
tolerance and greater perception of pain stimuli as unpleasant in African Americans and Hispanics compared with Caucasians (2.5)⁵,⁶,⁷,⁸. Reduced pain tolerance to experimental pain in African Americans supports findings in a population of chronic pain patients that showed similar pain intensity but increased perception of pain unpleasantness in African Americans compared with Caucasians⁹. Asians similarly demonstrate increased sensitivity to pain¹⁰.

2.3 Pain sensitivity by gender. The ability to perceive electrical stimulation as pain (threshold) and greatest tolerable level (tolerance) were tested in 20 healthy adults. Both pain threshold and tolerance were significantly higher in men (P<0.05). (Based on Walker JS, Carmody JJ, 1998³.)

2.4 Analgesic response by gender. A: The effect of a single dose of intravenous morphine was tested in healthy adults (10 males and 10 females). The graphs show individual (blue lines) and mean (red lines) responses to electrical current stimulation. Baseline currents were similar between genders for pain threshold and tolerance. While concentrations of morphine and its metabolites were similar between genders, women demonstrated greater overall morphine potency, slower speed of analgesic onset, and longer duration of analgesic effect. These data support clinical observations of higher opioid use in males for acute pain than females. (Based on Sarton E, et al., 2000⁴.) B: Twenty healthy adults (10 males and 10 females) were similarly treated with ibuprofen or placebo and tested with electrical stimulation. Neither ibuprofen nor placebo affected pain threshold, while ibuprofen did affect pain tolerance. Pain tolerance was significantly increased with ibuprofen in men (P<0.05) and not different between ibuprofen and placebo in women. (Based on Walker JS, Carmody JJ, 1998³.)

Analgesics

Short-acting analgesics may be used to treat intermittent, severe pain flares, while long-acting or sustained analgesics and adjuvant therapies are effective for reducing persistent disabling pain. Opioids provide stronger analgesic potency for noninflammatory pain than nonopioid analgesics, like nonsteroidal anti-inflammatory drugs (NSAIDs), without risk from prostaglandin-related effects (2.6)¹¹. About 30% of primary care patients prescribed opioids for chronic pain,

however, demonstrate medication misuse or abuse, including reporting lost/stolen prescriptions, obtaining opioids from secondary sources, and repeatedly requesting early refills¹². While opioids are most effective in reducing non-neuropathic pain, they may also be used for disabling neuropathic pain, although pain reduction may be less and dose requirements may be higher (2.7)¹³,¹⁴.

2.5 Differences in pain response by race. A: Experimental pain testing was completed in healthy adults representing three ethnic groups: African American (N=63), Hispanic Americans (N=61), and non-Hispanic Caucasian Americans (N=82). Demographic factors were considered as covariates in analyses. There were no differences in pain threshold for heat or cold pain among genders (not shown). Both heat and cold pain tolerance, however, were similar for African Americans and Hispanics and significantly lower in both ethnic groups compared with non-Hispanic Caucasians (P<0.05). (Based on Rahim-Williams FB, et al., 2007⁸.) B: In a similar study, pain testing was performed in 40 healthy adults: 20 British Caucasians and 20 South Asians from India, Pakistan, and Bangladesh. Perception of cold and warm was similar between ethnicities, while pain thresholds were lower among Asians. Differences between Caucasians and Asians were significant for heat pain threshold (P=0.006) and showed a trend toward significance for cold pain threshold (P=0.057). (Based on Watson PJ, et al., 2005¹⁰.)

2.6 Analgesic potency ladder. This analgesic potency ladder is based on the World Health Organization (WHO) 3-step analgesic ladder. The WHO recommends matching analgesic potency with pain severity. Patients with mild pain are initially treated with therapies within the first rung of the ladder, including nonopioid analgesics and adjuvant therapy. Treatment for patients with moderate severity pain should include the addition of weak opioids, with strong opioids reserved for patients with severe pain. The effectiveness of this approach was validated in a 10-year prospective study with cancer pain patients. Although 3 in 4 patients required weak or strong opioids, pain relief was shown to be equally effective in each step of the ladder when therapy was initiated with analgesic potency matched to pain severity. LA: long-acting; NSAID: nonsteroidal anti-inflammatory drug; TCA: tricyclic antidepressant.

Antidepressants

In addition to mood-enhancing properties, antidepressants offer potent analgesic effects. A variety of neural mechanisms explain the analgesic properties of antidepressants (Table 2.4)¹⁵. Antidepressants may be effectively used to treated chronic pain and frequently comorbid disturbances in mood and sleep.

Analgesic properties of antidepressants, however, are independent of their mood-relieving qualities, with analgesia occurring in patients without comorbid depression. Among different classes of antidepressants, tricyclics have the most potent analgesic effects (2.8)¹⁶. Among the newer antidepressants, serotonin and noradrenergic reuptake inhibitors, such as venlafaxine and nefazodone, and noradrenergic and specific serotonergic antidepressants, such as mirtazapine, offer the most promise for providing analgesia. Both of these classes of antidepressants affect α₂-adrenergic receptors and κ₁,κ₃, δ-opioid receptors, which may contribute to their analgesic properties¹⁵.

2.7 Opioid efficacy for neuropathic pain. Opioids may be effectively used to reduce neuropathic pain. Total pain relief was evaluated in 4 single-dose studies in which 168 patients received doses of opioid (A). Pain relief occurred with both groups, although relief was significantly better in patients with non-neuropathic pain (P=0.02). (Based on Cherny NI, et al., 1994¹³.) In a second study (B), the dosage of opioid buprenorphine necessary to reduce pain by at least 50% was compared in 21 patients who were treated for non-neuropathic postoperative thoracic surgery pain and 1 month later for post-thoracotomy neuropathic pain. While pain reduction was successfully achieved for both acute non-neuropathic pain and subsequent neuropathic pain, the opioid dosage required to achieve similar pain relief was significantly higher for the neuropathic pain (P<0.001). (Based on Benedetti F, et al., 1998¹⁴.)

Table 2.4 Analgesic effects from antidepressants

•	Presynaptic effects
–	Inhibition of noradrenaline reuptake
–	Inhibition of serotonin reuptake
•	Postsynaptic
–	Block α-adrenergic receptors
–	Block histamine receptors
–	Block cholinergic receptors
•	Induce opioid release
•	NMDA antagonism
•	N-type calcium channel blockade
NMDA: N-methyl-D-aspartate

2.8 Effects of antidepressants on diabetic neuropathy pain. Fifty-seven patients (59% male; median age = 58 years) with painful diabetic neuropathy were randomized to treatment with amitriptyline, despiramine, fluoxetine, or placebo in two double-blind studies. Mean daily doses were 105 mg amitriptyline, 111 mg despiramine, and 40 mg fluoxetine. The graph shows the percentage of patients receiving each treatment who experienced moderate or better pain relief. Pain relief was superior to placebo for both tricyclic antidepressants (P<0.05) but not fluoxetine. There were no significant differences in efficacy between the two tricyclics. (Based on Max MB, et al., 1992¹⁶.)

2.9 Antiepileptics for neuropathic pain. In a controlled, pilot study, 25 patients with diabetic neuropathy were randomized to treatment with gabapentin (mean dosage = 1,565 mg daily) or amitriptyline (mean dosage = 59 mg daily). At least moderate pain relief was experienced by 52% with gabapentin and 67% with amitriptyline. The graph shows changes in pain severity from baseline for patients completing the full 6 weeks of treatment. A reduction of 0.35 represents a decrease from moderate to mild pain. There were no significant differences in pain reduction between gabapentin and amitriptyline. These data support that both tricyclic antidepressants and antiepileptics can be effective therapies for neuropathic pain. (Based on Morello CM, et al., 1999¹⁷.)

Neurostabilizing antiepileptics

Antiepileptic drugs with neurostablizing properties reduce neuronal excitability by blocking sodium and calcium channels and acting as GABA mimics. Antiepileptics, such as gabapentin, pregabalin, carbamazepine, baclofen, valproate, topiramate, and others, provide modest analgesic benefit and reduction of neuropathic pain and chronic headaches. Pain relief with antiepileptics is similar to that achieved with tricyclic antidepressants (2.9)¹⁷.

Muscle relaxants

Most muscle relaxants or antispasmodic medications offer minimal long-term benefit for chronic pain. Tizanidine has been shown to reduce pain and sleep disturbance in patients with chronic headache and neuropathic pain. Tizanidine acts as an alpha 2-adrenergic receptor agonist, similar to the analgesic mechanism for clonidine.

Topical agents

Effective topical agents for neuropathic pain include 5% lidocaine patches and capsaicin cream (2.10, 2.11)¹⁸. In addition to reduction in neuropathic pain, these treatments also provide minimal systemic adverse effects.

Pain medications during pregnancy

Selection of medications prescribed to women capable of childbearing is influenced by medication safety during pregnancy (Table 2.5). Gabapentin may be used during attempted conception and early pregnancy. Because gabapentin may adversely affect development of the fetal bony
growth plate, it should be discontinued as pregnancy progresses. Opioids are best limited to infrequent, intermittent use. Patients who have been chronically using daily opioids during mid-to-late pregnancy must continue daily opioids because of the risks of fetal mortality and premature labour associated with intrauterine fetal opioid withdrawal¹⁹.

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