Managing Chronic Pain Syndromes

Release Date: March 1, 2016

Expiration Date: March 31, 2018

FACULTY:

Donna M. Lisi, PharmD, BCPS, BCPP, PRS
Clinical Pharmacist
Somerset, New Jersey

FACULTY DISCLOSURE STATEMENTS:

Donna M. Lisi has no actual or potential conflicts of interest in relation to this activity.

Postgraduate Healthcare Education, LLC does not view the existence of relationships as an implication of bias or that the value of the material is decreased. The content of the activity was planned to be balanced, objective, and scientifically rigorous. Occasionally, authors may express opinions that represent their own viewpoint. Conclusions drawn by participants should be derived from objective analysis of scientific data.

ACCREDITATION STATEMENT:

Pharmacy
acpePostgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
UAN: 0430-0000-16-008-H01-P
Credits: 2.0 hours (0.20 ceu)
Type of Activity: Knowledge

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Payment of $6.50 required for exam to be graded.

TARGET AUDIENCE:

This accredited activity is targeted to pharmacists. Estimated time to complete this activity is 120 minutes.

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DISCLAIMER:

Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients' conditions and possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities.

GOAL:

To educate the pharmacist on the mechanism of chronic pain syndromes and on the risk factors, signs, and symptoms, and pharmacologic management of diabetic neuropathy, HIV/AIDS neuropathy, and postherpetic neuralgia.

OBJECTIVES:

After completing this activity, the participant should be able to:

  1. Describe the pathophysiology of pain syndromes.
  2. Explain the mechanism for the development of painful diabetic peripheral neuropathy (PDPN), HIV/AIDS neuropathy (H/A-N), and postherpetic neuralgia (PHN).
  3. Specify risk factors for PDPN, H/A-N, and PHN.
  4. Review the current literature on the management of PDPN, H/A-N, and PHN.
  5. Differentiate between the treatment strategies for the management of PDPN, H/A-N, and PHN.

ABSTRACT: Chronic pain syndromes are very common and debilitating. Acute pain can evolve into chronic pain through central sensitization. Among the chronic pain syndromes that pharmacists may encounter are diabetic peripheral neuropathy, HIV/AIDs neuropathy, and postherpetic neuralgia. The risk factors, signs and symptoms, and management of these conditions are discussed. Pharmacists can use their expertise in pain management to help optimize the pharmacotherapy regimens of patients experiencing a chronic pain syndrome.

Chronic pain syndrome (CPS) refers to a poorly defined condition that is associated with pain lasting a minimum of 3 months to longer than 6 months. It is accompanied by a constellation of symptoms that are unamenable to the medical model of care. Owing to the complexity of CPS, it is best managed via a multidisciplinary approach.1 Pharmacists can play a major role in improving the quality of life of patients suffering from a CPS.

TYPES OF PAIN SYNDROMES

There are numerous types of pain syndromes. The International Association for the Study of Pain (IASP) has identified approximately 102 chronic pain syndromes.2

THE PATHOPHYSIOLOGY OF CHRONIC PAIN

Research into the pathophysiology of chronic pain has focused on central pain mechanisms.3 Emerging data are demonstrating that pain syndromes are associated with a pathologic process of dysregulated nociception called central sensitization, which results in the transformation of acute pain into chronic pain and localized pain disorders into widespread pain disorders. Persistent nociceptive input leads to changes in the central nociceptive system, producing neuroplastic changes. In chronic pain, there is persistent activation of A delta and C fibers, which stimulate the release of neurotransmitters and neuromodulators such as substance P, nerve growth factor, calcitonin gene–related peptide, glutamate, and aspartate into the dorsal horn synapse. This results in hyperalgesia (i.e, increased pain in response to normally painful stimuli) and allodynia (i.e., pain in response to normally nonpainful stimuli). Environmental stressors such as early life trauma, physical trauma, infections, and emotional stress may trigger the development of central sensitization or central sensitivity syndrome. Alterations in gene expression may also contribute to chronic pain. Neuroimaging has demonstrated changes in areas of the brain secondary to chronic pain. As a result, chronic pain itself is considered a disease.3-6

MANAGEMENT OF PAIN SYNDROMES

The management of all pain syndromes is beyond the scope of this paper. This paper will focus on the management of diabetic peripheral neuropathy (DPN), HIV/AIDS neuropathy (H/A-N), and postherpetic neuralgia (PHN).

Diabetic Peripheral Neuropathy

According to the CDC, 29.1 million people (or 9.3% of the population) have diabetes mellitus, of which only about 21 million have been diagnosed.7 Painful DPN (PDPN) is defined as pain arising as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes.8-12 Overall, in patients with type 1 diabetes, the incidence of DPN is 2,800 per 100,000 person-years compared with 6,100 per 100,000 person-years in those with type 2 diabetes.11

Definition: DPN (also referred to as diabetic sensorimotor polyneuropathy, diabetic distal symmetric polyneuropathy, sensory neuropathy, and autonomic neuropathy) is a symmetrical, length-dependent sensorimotor polyneuropathy due to metabolic and microvessel alterations, which are secondary to chronic hyperglycemia and cardiovascular risk covariates.8,9,13

Risk Factors: It is thought that long-standing, uncontrolled diabetes results in metabolic derangements due to increased polyol flux; accumulation of advanced glycosylated end products, which cause demyelination, axonal degeneration, reduction in conduction velocity, basement membrane thickening, and capillary endothelial damage; oxidative stress, which aggravates nerve damage; and lipid alterations, which result in alterations of the microvessels of the peripheral nerves and thereby also contribute to peripheral vascular disease. This, coupled with a deficiency of nerve growth factors and insulin-like growth factors, results in impaired neuronal regeneration. Central sensitization also contributes to PDPN. Risk factors associated with PDPN are listed in TABLE 1.12

Signs and Symptoms: Initially, symptoms of PDPN may be per sistent or intermittent. PDPN occurs in a stocking-glove pattern and typically starts in the toes and spreads proximally. Other signs and symptoms that are associated with PDPN are included in TABLE 2.8,11,14,16 Weakness, especially decreased distal lower extremity strength, is a late sign of the disease.11 These symptoms appear to worsen in the evening. Altered sensation can lead to foot ulcers, infections, amputations, balance disturbances, and falls. Pain can be assessed using the Neuropathic Pain Symptom Inventory.17

Management: The evidence-based guidelines disseminated in 2011 by the American Academy of Neurology (AAN), the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), and the American Academy of Physical Medicine and Rehabilitation (AAPMR) classify recommendations as Level A (established as effective, ineffective, or harmful for the given condition in a specified population); Level B (probably effective, ineffective or harmful for the given condition in a specified population); Level C (possibly effective, ineffective, or harmful for the given condition in a specified population); and Level U (data inadequate or conflicting given current knowledge; treatment is unproven). The guidelines indicate that the placebo response for pain in PDPN ranges from 0% to 50%, which further muddies the issue of therapeutic efficacy. Another concern with the studies on adjuvant analgesics in PDPN is that most trials were of short duration, being only 2 to 20 weeks long, while PDPN is a chronic disease.9

The only drug recommended with Level A evidence for use in PDPN in the AAN/AANEM/AAPMR guidelines is pregabalin 300 to 600 mg/day. Other drugs listed in the AAN/AANEM/AAPMR guidelines for the management of PDPN can be found in TABLE 3.9,18

Other guidelines or statements that have addressed the management of PDPN (or neuropathic pain with a specific section on DPN) include the European Federation of the Neurological Societies Task Force (EFNS), the Toronto Diabetic Neuropathy Expert Group, and the Canadian Pain Society (TABLE 3).19-21

Drugs given a first- and second-line recommendation by the Toronto Diabetic Neuropathy Expert Group can be found in TABLE 3.20 Other drugs also recognized for proven efficacy in PDPN include membrane stabilizers; the antioxidant alpha-lipoic acid; and capsaicin. There is a paucity of information on the use of combination regimens in PDPN.

In 2015, the Agency for Healthcare Research and Quality (AHRQ) examined the effectiveness of treatments for DPN. It stated that new trials involving the use in DPN of topical ketamine; clonidine; cannabinoids; dextromethorphan/quinidine; high-dose capsaicin patch; aldose reductase inhibitors such as ranirestat and epalrestat; the antioxidant, alpha-lipoic acid; the antinerve growth factor antibody, fulranumab; the protein kinase C-beta inhibitor, ruboxistaurin; ganglisoides; and prostaglandin E1 in DPN have become available, but it does not offer guidelines for treatment.15

A recent review in the The Journal of the American Medical Association (JAMA) stated that the primary medications with high-quality evidence supporting their use in PDPN include TCAs (tricyclic antidepressants; e.g., amitriptyline, nortriptyline, imipramine), serotonin-norepinephrine reuptake inhibitors (SNRIs; e.g., duloxetine, venlafaxine), and voltage-gated calcium channel ligands (e.g., gabapentin and pregabalin). It is difficult to determine comparative efficacy, as there are few to no head-to-head clinical trials. If a drug from one class fails, it is reasonable to try a medication from a different class. It is recommended to attempt trials of at least two medications from each of the three classes (TCAs, SNRIs, and voltage-gated calcium channel ligands) before utilizing lower-evidence medications (e.g., tramadol or lidocaine patches).11

A systematic review and meta-analysis on pharmacotherapy for neuropathic pain (not specifically PDPN) was conducted by the Special Interest Group on Neuropathic Pain (NeuPSIG) of the IASP. It recommended that TCAs, SNRIs, voltage-gated calcium channel ligands, and topical lidocaine should be considered for first-line therapy (Grade A recommendation) for PDPN. If patients have an inadequate response to these first-line drugs either alone or in combination, opioids or tramadol can be used as second-line therapy either alone or in conjunction with a first-line agent (Grade A recommendation). Third-line agents for which substantially less evidence of efficacy exists include carbamazepine, lamotrigine, oxcarbazepine, topiramate, valproic acid, bupropion, citalopram, paroxetine, mexiletine, N-methyl-D-aspartate receptor antagonists, and topical capsaicin (Grade B recommendation). If pain relief is still inadequate, a pain specialist should be consulted.22

Finnerup et al found that the NNT (number needed to treat) for SNRIs (i.e., duloxetine) was 6.4; for pregabalin, 7.7; for gabapentin, 7.2 (including extended-release and enacarbil forms); and for capsaicin high-concentration patches, 10.6.23 The NNT was lower for TCAs, opioids, tramadol, and botulinum toxin A; it was undetermined for lidocaine patches. These findings were based on moderate to high quality of evidence. The researchers recommended the use of TCAs, SNRIs, pregabalin, and gabapentin as first-line therapy; lidocaine patches, capsaicin high-concentration patches, and tramadol as second-line therapy; and opioids and botulinum toxin A as third-line therapy for PDPN.23

Snedecor et al performed a network meta-analysis on pharmacologic therapies for PDPN. They found that amitriptyline and gabapentin produced similar pain relief and that lidocaine’s efficacy was similar to that of amitriptyline, capsaicin, gabapentin, and pregabalin in pain reduction. Dose-dependent reduction in pain was observed for duloxetine (60 mg/day and 120 mg/day offered greater pain relief than 20 mg/ day) and pregabalin (300 mg/day or 600 mg/day offered greater pain relief than 150 mg/day).24

However, despite all of these therapeutic options, a reduction in pain of only 30% to 50% is expected in most patients taking maximum doses of medication in PDPN. Adverse effects limit maximal benefit.25

HIV/AIDS Neuropathy

HIV affects approximately 33 million people worldwide.26 Currently, in the United States, >1.2 million people are infected with HIV. In the past 10 years, the number of people living with HIV has increased as a result of HAART (highly active antiretroviral therapy).27 Owing to the lack of standardized diagnostic criteria for H/A-N, the prevalence of H/A-N ranges from 1.2% to 69.4% among HIV patients (depending on the study) for a rate of 0.7 to 39.7/100 person-years.28 Some studies have reported the prevalence of neuropathy to be closer to 20% to 57% among those infected with HIV/AIDS.29 At the time of HAART initiation, 13% to 38% of HIV patients may have preexisting peripheral neuropathy or documented neuropathic signs.29,30

Definition: HIV/AIDS distal symmetrical polyneuropathy is the most common neurologic complication of HIV. H/A-N may present in a variety of forms, including acute and chronic inflammatory demyelinating polyneuropathy, autonomic neuropathy, polyradiculopathy, mononeuropathies, mononeuritis multiplex, cranial neuropathies, and amyotrophic lateral sclerosis–like motor neuropathy.31 There is no gold standard definition for H/A-N. This distal symmetrical polyneuropathy is a length-dependent, predominantly small-fiber sensory neuropathy that mainly affects the lower extremities.29,32

Risk Factors: H/A-N can be due to either antiretroviral-induced neuropathy or to the effects of the virus itself. The antiretroviral drugs most often associated with a peripheral neuropathy are the nucleoside analogue reverse transcriptase inhibitors (NRTIs), also known as dideoxynucleoside agents (i.e., the d-drugs), such as didanosine, stavudine, and zalcitabine. These drugs exert their harmful effects by disrupting neuronal mitochrondrial synthesis.29,33 An adjusted hazard ratio for possible drug-induced neuropathy from stavudine is 4.16.30 Zalcitabine was discontinued by the manufacturer in 2006.34 Further, the World Health Organization has called for the phasing out of the use of stavudine in the treatment of HIV.29 Other risk factors associated with H/A-N are listed in TABLE 1.29,30,35

Recently, genes have been identified that affect mitochondrial function and the inflammatory response associated with HIV infection. These appear to enhance the risk of neuropathy in persons exposed to neurotoxic antiret-roviral agents. Polymorphisms in mitochondrial haplotype T (mtDNA), which are primarily found in patients of European descent, are associated with increased risk of H/A-N; this is potentiated by the neurotoxic effects of NRTIs. Polymorphisms in the L1c mitochondrial haplo-types have been associated with neuropathy in African Americans. Polymorphisms in nuclear DNA (nDNA) (e.g., inhibition of DNA polymerase gamma) have also been seen in HIV/AIDS, and these affect mitochondrial function resulting in reduced synthesis of mitochondrial proteins needed for energy production and regulation of reactive oxygen species. There may also be alterations in the hemochromatosis gene, which regulates iron transport across membranes, affecting mitochondrial function in HIV/AIDs patients. Enhanced secretion of tumor necrosis factor alpha and polymorphisms in the major histocompatibility complex region of chromosome 6 increase risk of neuropathy in HIV/AIDS, whereas polymorphism of chromosome 5 in the gene encoding for proinflammatory cytokines is associated with reduced risk of neuropathy in this population. This latter property only seems to apply to patients who develop neuropathy within 6 months of starting combination HAART. There is also evidence supporting a genetic component for the susceptibility and intensity of pain in H/A-N. These genetic polymorphisms appear to vary depending on the ethnic group analyzed.29

HIV proteins produce direct and indirect damage to peripheral nerve fibers and dorsal root ganglion cells, which some feel is more pronounced in patients with lower CD4+ T-cell counts, longer duration of systemic illness, or AIDS illnesses.29 However, others report that the incidence and prevalence of H/A-N has either remained the same or increased since the introduction of combination HAART. This may indicate that the degree of immunosuppression may not play a significant role in the development of H/A-N. Rather, low levels of viral replication or immune reconstitution may be contributing to neurotoxicity.29,32 The risk of developing a peripheral neuropathy while on HAART appears to be 1% per year after the first year. It is generally low after the first 6 to 12 months of HAART with a peak effect seen within the first 90 days. One study with a 4.9-year follow-up found that the incidence of new-onset peripheral neuropathy in HIV patients was 11% or 2.12 per person-years; 12% had taken stavudine and 18% had been on isoniazid.30

Signs and Symptoms: Signs and symptoms of HIV/AIDS sensory neuropathy are found in TABLE 2.31,32,35,36 Pain has been observed in 50% to 90% of those with H/A-N, which is higher than that associated with other peripheral neuropathies, including PDPN.29 In the majority of HIV patients, the peripheral neuropathy reported was classified as grade 1/2.30 However, pain intensity increases with poor disease control and worsening nerve fiber injury.29

Management: H/A-N is difficult to manage, as the syndrome does not respond to the usual treatment for neuropathies. Compared with PDPN, neither symptomatic nor disease-modifying agents significantly improve symptomatology.19,21,31

Although there are no guidelines specific to H/A-N, the EFNS and the Canadian Pain Society guidelines do have a section on managing this condition (TABLE 3).19,21

According to the Canadian Pain Society, high-concentration (8%) capsaicin has a NNT of 6.2 in H/A-N; it is listed as a fourth-line agent. Although the cannabinoids are listed as third-line, the guidelines warn that their use requires close monitoring and is contraindicated in patients with a history of psychosis.21

According to NeuPSIG, TCAs, gabapentin, and lidocaine gel do not appear to be any more effective than placebo in H/A-N. It does not offer recommendations for effective therapies.22

Acetyl-L-carnitine use has demonstrated positive results in clinical trials in H/A-N. It is thought to act by enhancing neurotrophic support of sensory neurons, which may produce symptomatic relief and nerve regeneration.33

In a systematic review and meta-analysis on the pharmacologic management of pain, topical capsaicin was the only treatment demonstrating a meaningful treatment response, whereas memantine was associated with worsening of pain in H/A-N.37

Patients with HIV who are also receiving isoniazid for tuberculosis treatment or prophylaxis should receive pyridoxine 25 mg/day to help reduce the risk of developing peripheral neuropathy.30

Postherpetic Neuralgia

Varicella zoster virus (also known as herpes zoster or shingles) remains dormant in the dorsal root ganglion cells following a bout of chickenpox (or varicella).38 PHN is persistence of the pain of shingles longer than 3 months after the resolution of the rash.39,40 However, others define PHN as pain occurring anytime from 1 to 6 months following viral infection. The prevalence of PHN is 10% to 21% in those who have had a zoster infection.39,41 This prevalence may increase to >30% in those aged >80 years.42 The pain associated with PHN significantly interferes with daily functioning.43 The duration of symptomatology in PHN is highly variable with approximately 50% of patients symptomatic 12 months after onset.39 Both central and peripheral mechanisms are thought to be involved in the propagation of pain in PHN with sensitization due to the release of inflammatory mediators and deafferentation of the dorsal root ganglion. Spontaneous pain, allodynia, and hyperalgesia are the result of sensitization of the peripheral and/or central nervous systems.44

Risk Factors: Older age may be the most important risk factor for PHN owing to the decreases in cell-mediated immunity with aging.44 Among persons aged >60 years, 13% of those who develop herpes zoster will suffer from PHN, and among these, about 6% will have persistent and unrelieved pain.40 Relative risk estimates per 10-year increase in age for PHN vary from 1.22 to 3.11, depending on the study.43

Other risk factors for PHN are listed in TABLE 1.38,40,41,43,45,46 It is thought that the greater severity of acute pain may indicate more substantial neural damage.41 Prodromal pain and severe acute pain are associated with relative risk factors of 2.29 and 2.23, respectively, for developing PHN.43 Depression and cancer do not increase the risk of PHN. Gender appears to have a controversial risk role, with age >60 years being protective for females whereas age <60 years is associated with an increased risk of PHN.43 Longer rash duration at presentation of zoster may possibly be protective against PHN, reducing the risk of this painful syndrome by over 20% for every day that the rash is present.43 Location in the ophthalmic branch of the trigeminal nerve as well as greater neurosensory disturbances are less-well-proven risk factors.44

Genetic factors appear to serve as risk factors, as HLA-A*33 and HLA-B*44 appear to be involved in the development of PHN. Depletion of HLA-A*02 and HLA-A*40 may also be a risk factor.38

Signs and Symptoms: The pain associated with PHN typically is one of three types: spontaneous pain that is ongoing, such as continuous burning pain; paroxysmal shooting or electric-like pain; and evoked sensations that are grossly magnified responses to light touch and other innocuous or noxious stimuli.46

Other signs and symptoms of PHN can be found in TABLE 2.42 PHN pain is located in the same dermatomal distribution as the initial zoster rash. More than 70% of patients with PHN complain of a burning sensation and mechanical allodynia (i.e., brush-evoked pain). Ophthalmic and trigeminal involvement occurs more frequently in older patients.42 The Zoster Brief Pain Inventory is a disease-specific pain assessment tool.47

Management: Management of PHN is difficult, as <50% of patients respond to treatment.46,48 Therefore, prevention of the initial herpes zoster infection is key. This can be achieved through the use of the zoster vaccine. Among older adults aged 60 to 69 years, the zoster vaccine decreases the chance of developing PHN by 66%.40 It has been shown that even if herpes zoster infection occurs following administration of the zoster vaccine, women experience a lower risk of developing PHN; this effect was not seen in men.49

The AAN published guidelines on the treatment of PHN in 2004; this makes them a bit outdated. Their recommendations can be found in TABLE 3. The guidelines do not make recommendations on the long-term effects of any treatment.39

The EFNS and Canadian Pain Society guidelines on the pharmacologic management of neuropathic pain can be found in TABLE 3.19,21 A trial of 2 to 4 weeks should be tried before switching agents.19

According to the Canadian Pain Society, the administration of antivirals, gabapentin, or corticosteroids during active herpes zoster infection do not decrease the risk of developing PHN.40 Other sources state that antivirals can reduce the overall duration of pain during the initial episode and the incidence of PHN.50

Evidence-based recommendations by the NeuPSIG show that whereas TCAs, gabapentin, pregabalin, topical lidocaine, opioids, and tramadol have demonstrated benefit in PHN, venlafaxine is associated with inconsistent or negative results for this condition. Lidocaine patch 5% and lidocaine gel are useful in patients with PHN and allodynia. Findings on valproic acid and capsaicin in the management of PHN have been mixed or inconsistent.22

A guidelines review on the management of PHN advised the following: voltage-gated calcium channel ligands, TCAs, and the topical 8% capsaicin patch as first-line therapy, with opioids and tramadol as second- or third-line agents.51

A recent clinical practice paper on PHN in the New England Journal of Medicine recommended initiating treatment with 5% lidocaine patches. If the response is inadequate, pregabalin or gabapentin may be added. If the response is still not optimal or if the patient is experiencing bothersome side effects, the recommendation is to change to a TCA.46

A systematic review and meta-analysis of pharmacologic therapies for pain, including PHN, found that all guideline-recommended treatments were more effective than placebo when assessed using the numerical rating scale and the endpoints of >30% and >50% pain reduction.37

Despite the availability of management guidelines for PHN, they are not often followed. It was found that initially only about 25% of patients receive a first-line recommended therapy for the management of PHN, and patients stayed on these initial treatments an average of less than 2 months.52

CONCLUSION

Pain syndromes are very common and affect both younger and older patients. DPN, H/A-N, and PHN adversely affect a patient’s quality of life. Pharmacists need to be knowledgeable about the presentation and management of pain syndromes in order to help optimize the pharmacologic management of their patients.

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