Learning Objectives/Outcomes:After participating in the CME/CNE activity, the provider should be better able to:

1. Examine the epidemiology of HIV/AIDS-related neuropathic pain.

2. Evaluate 2 methods for assessment of HIV/AIDS-related neuropathic pain.

3. Identify 2 effective system-level approaches for managing pain in patients with HIV/AIDS.

Human immunodeficiency virus (HIV) is a chronic disease that requires lifelong treatment. Improvements in early detection and combination antiretroviral therapy have led to increased survivorship, with an estimated 1.1 million people in the United States currently living with HIV and acquired immunodeficiency syndrome (AIDS). However, the gains in survivorship have been coupled with the acquisition of chronic comorbidities, including chronic pain. As a common comorbid condition among people living with HIV and AIDS (PLWHA), chronic pain occurs in up to 90% of patients and is associated with greater odds of functional impairment and suboptimal retention in HIV primary care. In particular, neuropathic pain carries a higher burden for patients and is often treatment-resistant. As with other patient populations with chronic pain, multimodal treatment with pharmacologic and nonpharmacologic therapies is recommended, with close attention to the high risks associated with opioid analgesic use.

First, a word about an abbreviation we will use in this article: the initialism "PLWHA" stands for these words: people living with HIV and AIDS. It is actually a compound abbreviation, in that it contains an initial letter of one more initialism-the H stands for HIV-and the initial letter of an acronym-the A stands for AIDS.

Epidemiology of HIV/AIDS-Related Pain

Compared with uninfected individuals, chronic pain is more common in PLWHA, with estimated prevalence ranging from 25% to 90%, depending on the cohort, type of pain, location, and severity.1,2 A systematic review of HIV-related pain demonstrated that the prevalence of pain ranged from 54% to 83% using a 3-month recall period, which did not vary significantly across the severity of disease, and was reported by a majority of patients to be of moderate-to-severe intensity.3 Although the impact of pain on daily function was reported as moderate, the authors reported a marked undertreatment of pain among patients with HIV/AIDS. In addition, PLWHA with chronic pain, compared with their peers without pain, are at much greater odds of functional disability and reduced quality of life, suboptimal adherence to antiretroviral therapy (ART), poor retention in HIV/AIDS care, and practicing HIV risk behaviors with potential to transmit HIV to others and to cause damage to their own health from exposure to other pathogens.4-6

Although access to and provision of pain management to reduce suffering and limit disability are a national priority,7 increased attention has recently been focused on informing providers about the risks of opioid analgesics and the need for multimodal treatment for patients with chronic pain, on using pharmacologic and nonpharmacologic strategies to manage pain, and on increasing patient coping skills and reducing maladaptive pain behaviors.8 However, despite these focused efforts, PLWHA are more likely to be prescribed opioids by their health care providers than are individuals in the general population.9 Of even greater concern, the prevalence of opioid use disorders and opioid-related mortality is higher among PLWHA than in the general population, with up to 62% of PLWHA having high-risk opioid-related behaviors (ie, high daily dosage, early refills, overlapping prescriptions, and/or multiple prescribers) in some studies.10,11

Characteristics of HIV/AIDS-Related Pain

Pain is one of the most common symptoms reported by PLWHA,12 and patients often have multiple types of pain and body regions affected by pain.13 Pain may be directly related to HIV infection, or associated with premorbid conditions, antiretroviral medications or other treatments, and with normal degenerative processes.14 A 1-year analysis of 638 patients who were receiving standard-of-care antiretroviral therapy in a large primary care HIV clinic found that the most common pain diagnoses were degenerative musculoskeletal disorders, such as degenerative spinal disease and osteoarthritis, neuropathic pain, and headache disorders.13

Peripheral neuropathy is the most frequent neurologic complication associated with HIV infection and affects up to 30% of people with AIDS.14 Patterns of HIV/AIDS-related neuropathy can affect peripheral sensory and motor nerves, cranial or thoracic nerves, or autonomic nerves, and may affect 1 nerve at a time or multiple nerves. The most common forms are highlighted in Table 1.

Table 1. Common Patterns of HIV/AIDS-Related Neuropathy

HIV/AIDS-related neuropathies may occur due to neurotoxicity from viral gene products and/or inflammatory activation to HIV.15 Indirect neurotoxic effects of HIV may be mediated by glycoprotein (gp)120, a protein exposed on the surface of the HIV envelope, which activates macrophages and Schwann cells resulting in neuroinflammation.16 In addition, mitochondrial DNA damage may contribute to the symptoms of neuropathic pain.17

Assessment of HIV/AIDS-Related Pain

Due to the high prevalence of pain in patients with HIV/AIDS, practitioners should incorporate pain assessment and management in the comprehensive HIV/AIDS care model,18 with routine pain assessment at each patient encounter.13 The process of building a differential diagnosis should include the taking of a focused medical history, psychosocial assessment, and physical examination. The medical history may identify syndromes that require intervention, such as herpes zoster, bacterial infection, or toxic neuropathy. Distress and perceived disability levels should be determined, to identify changes in the patient's level of function or associated symptoms that may indicate development of depressive disorder.14

As with all routine pain assessments, the onset, location(s), frequency, severity, and duration of pain should be documented along with any alleviating and aggravating factors. Sensory characteristics should be assessed using descriptors such as burning, stinging, stabbing, or gnawing that may indicate neuropathic pain as opposed to common musculoskeletal pain conditions.

In an exploratory study among 49 women with HIV and chronic pain of primarily neuropathic or nociceptive qualities, the women with neuropathic pain reported significantly higher pain frequency, interference with activities and emotions, and levels of catastrophizing and depression.19 The authors suggest that given the significant burden of neuropathic pain on psychological states in women with HIV, psychosocial support services should be considered in the provision of treatment.

There is no gold standard for diagnosis of HIV/AIDS-related peripheral neuropathy. However, several clinical tools have been developed for other clinical pain conditions that may be useful in the context of HIV/AIDS-related pain. The Total Neuropathy Score20 and the Brief Peripheral Neuropathy Screen21 have been suggested as especially relevant for this patient population.15 The Total Neuropathy Score provides a composite score based on grading of sensory, motor, and autonomic symptoms, and grading of pin and vibration sensations, muscle strength, deep tendon reflexes, sural and peroneal amplitudes assessed by nerve conduction studies, and quantitative sensory testing of vibration.20

The Brief Peripheral Neuropathy Screen does not require neurophysiologic testing and can be performed quickly in the clinical setting. Compared with the Total Neuropathy Score, its sensitivity and specificity are 35% to 49% and 88% to 90%, respectively, with a positive predictive value of 72%.22,23

Due to the overlap in symptom presentation and possibility of comorbid infections that may be underlying the presentation of neuropathic pain, the practitioner may want to consider laboratory studies, cerebrospinal fluid analysis, and neuroimaging. Common laboratory analysis in the initial evaluation of neuropathic pain may include basic metabolic panel, liver function tests, hemoglobin A_1C, vitamin B₁₂, folate, thyroid function tests, and hepatitis C virus serology.15

Similar to other forms of neuropathic pain, HIV/AIDS-related neuropathies are commonly treated with anticonvulsants (gabapentin, lamotrigine, pregabalin), local anesthetics (capsaicin, lidocaine), antidepressants (duloxetine, amitriptyline), and analgesics (nonsteroidal anti-inflammatory drugs, acetaminophen, opioids).

Other evidence-based therapies for chronic pain, such as acupuncture, massage, manipulation therapy, mindfulness, meditation, and relaxation therapies-and movement therapies (yoga and tai chi)-may also be effective. However, as noted in a recent systematic review, very few studies have focused on HIV/AIDS-related pain or neuropathic pain in particular.24

To address this gap, a recent study evaluated an exercise intervention on pain outcomes associated with distal symmetrical polyneuropathy, a prevalent, disabling, and treatment-resistant complication of HIV and/or HIV treatment.25 In this multicenter randomized pretest-posttest study, recruited patients were on antiretroviral therapy for at least 6 months, referred for rehabilitation after HIV-related distal symmetrical polyneuropathy diagnosis, and were able to participate in weekly exercise sessions for 12 weeks. Participants (n = 154) were randomized to aerobic exercise (AE), progressive resistance exercise (PRE), or control. Exercises were conducted under supervision for 30 minutes on alternate days, 3 times per week for 12 weeks. The control group attended HIV education sessions and counseling on dietary and exercise recommendations, whereas the other groups were simply exercising.

The AE group had significant decreases in pain (P < 0.001) with large effect sizes from baseline to 6 weeks, 6 to 12 weeks, and baseline to 12 weeks. Significant decreases with large effect sizes were also noted after intervention for PRE. There were no differences in pain over time in the control group. Post hoc analysis showed a significant difference with small effect size at 6 and 12 weeks between AE and PRE, between AE and control, and PRE and control, with the results showing a slight superiority of the PRE intervention compared with moderate aerobic exercise. However, participants in both the PRE and AE groups reported a significant reduction in pain at 6 and 12 weeks, compared with the control group. No adverse events were reported. The study demonstrates that moderate exercise is safe and effective in patients with distal symmetrical polyneuropathy when used as an adjunct to pharmacologic therapy.

In a pilot study that randomized 32 patients with HIV with chronic neuropathic or musculoskeletal pain to mindfulness-based stress reduction (MBSR) versus health education control, there was no effect of group assignment observed.26 However, at 3-month follow-up, 79% of MBSR participants were still practicing, and pain intensity had improved as compared with the control group, which showed a higher intensity of pain from baseline. More research studies to investigate the effectiveness of mind-body interventions and nonpharmacologic strategies for managing pain are needed for patients with HIV/AIDS.

Shared Neurobiological Mechanisms of Chronic Pain and Substance Use Disorders

Substance use disorders are common in the general population and have increased due to the liberal use of prescription opioids.27 Similar to the general population, substance use disorders may be preexisting in PLWHA or be iatrogenically induced from prescription opioids. The probability of long-term opioid use increases after as little as 5 days of prescribed opioids as the initial treatment of pain, and the rate increases when long-activating opioids are used as initial treatment.28 The brain reward-and-reinforcement circuitry, which is involved in addiction, includes dopamine neurons in the ventral tegmental area (VTA), the nucleus accumbens (NAc), and the striato-nigro-striatal circuit linking the NAc shell to the dorsal striatum.29 Increased levels of dopamine in the NAc occur with natural reward and drugs of abuse and other positive subjective experiences such as analgesia.30 The pathway activity from the VTA to the NAc is modulated by other cortical and subcortical structures, including the pain neurocircuitry.31

The pain matrix as described by Melzack32 and shown in Figure 1 posits that chronic pain is generated from the interpretation of subjective experiences through a network of neurons known as the neuromatrix. These areas of the brain were examined in a small study that compared morphometric measures between HIV-positive individuals (n = 31) and seronegative individuals (n = 35).33 Compared with seronegative individuals, patients with HIV had smaller surface areas in the prefrontal pars triangularis and right anterior cingulate cortex and small subcortical regions, consistent with prior studies. However, higher pain scores in HIV participants were associated with larger cortical areas, thinner cortices, and larger subcortical volumes, suggesting abnormal pain responses located in the affective region of the pain matrix. These findings suggest that affective symptoms may influence pain perception in patients with HIV and should be treated along with physical symptoms.

Figure 1. The pain matrix. The brain regions that comprise the pain matrix are grouped into 3 different components: sensory or discriminative, affective, and associative. The sensory component comprises the thalamus and somatosensory cortex. The affective component includes the brainstem, thalamus, limbic system (amygdala, hippocampus, and basal ganglia), prefrontal cortex, anterior cingulate cortex, and insula. The associative component includes the posterior parietal cortex. Reprinted with permission from

In a secondary analysis of the Intervention for those Recently Informed of their Seropositive Status (IRISS) study, the effect of the positive-affect skills intervention was evaluated on pain prevalence, pain interference, and use of opioid analgesics.34 The IRISS intervention is grounded in the revised Stress and Coping Theory35 and the Broaden-and-Build Theory of positive emotion.36

For the study, English- and Spanish-speaking individuals diagnosed with HIV within the past 12 weeks were recruited from HIV clinic and were randomized to receive IRISS (n = 80) or a time- and attention-matched control (n = 79). Both groups received 5 weekly in-person individual sessions with a facilitator and a sixth session conducted by telephone. IRISS participants received instruction and practice in 8 positive-affect skills (noticing and capitalizing on positive events, gratitude, mindfulness, positive reappraisal, personal strengths, goal attainment, and acts of kindness). The control group participated in supportive personal interviews on topics such as life history, health history, and personality.

All participants were followed up for repeat data collection at 5, 10, and 15 months postintervention. Although there were incon-clusive findings on the effect of the intervention on headache, musculoskeletal pain, and neuropathic pain, the results suggest that, as pain prevalence rises, positive-affect skills may reduce pain interference and prevent increased use of opioids in people living with HIV.

Several limitations of the study are noted, including the point that IRISS was not designed to improve pain management and robust pain measures were not used in the study, the reason (condition) for opioid prescription was not obtained, there were no physical (exercise, movement, or physical activity) aspects, and the study primarily included men recently diagnosed with HIV. Because pain conditions often affect women more often than men, the authors suggest that recruitment strategies should be modified in future studies, and they offer several recommendations for future trials.

As PLWHA are at higher risk of opioid use disorder than the general population,10,11 it is imperative that practitioners employ general precautions with reliable screening measures and a thorough medical history and physical examination. PLWHA with opioid use disorder may be treated for addiction with (1) naltrexone, an opioid antagonist; and (2) buprenorphine, a partial opioid agonist; or (3) methadone, a full opioid agonist similar to morphine, hydrocodone, or oxycodone. Buprenorphine and methadone target the [micro]-opioid receptor, have similar half-lives of 24 to 36 hours, and are both metabolized by cytochrome P450 enzymes.37

Risk of fatal overdose is increased when other central nervous system depressants, such as alcohol or benzodiazepines, are used. To investigate the impact of buprenorphine/naloxone treatment on HIV treatment adherence, the multisite BHIVES (Buprenorphine HIV Evaluation and Support) Initiative included 386 HIV-infected individuals eligible for buprenorphine treatment, who were followed up for 12 months, with outcomes obtained every 3 months and medical record review.38 Participants taking buprenorphine/naloxone for at least 3 of 4 quarters during a year were more likely to have initiated antiretroviral therapy and have achieved viral suppression (HIV RNA level <400 copies/mL) than those taking it less than 3 quarters. In addition, retention in treatment with buprenorphine/naloxone was associated with reduced use of opioids and stimulants and improvements in physical and mental quality of life.39,40

Interventions for Curbing Opioid Prescriptions and Use

Considering the high rate of comorbid pain conditions among PLWHA, opioid prescriptions among providers caring for patients with HIV/AIDS, and the suboptimal outcomes associated with high-dose opioids, it should be a national priority to identify ways to reduce the risk of opioid addiction while providing quality pain management.41-43 It has been observed that providers in general medicine, family medicine, internal medicine, nurse practitioners, and physician assistants are more likely to prescribe opioids compared with other specialty health care providers,9 so perhaps focusing interventions on these specialties may be one way to improve opioid prescribing. Another way would be to improve the prescription of evidence-based multimodal pain management strategies that include nonopioid analgesics and nonpharmacologic treatments,27 which is consistent with the National Pain Strategy and Centers for Disease Control and Prevention guidelines.7,8 However, in 1 study it was found that, instead of prescription for nonpharmacologic treatments, patients discontinuing opioid therapy were more likely to receive opioid taper, new nonopioid analgesics, or dose changes to an existing nonopioid analgesic medication, or be referred for specialty substance use disorder treatment.44 Voluntary opioid tapering using a 4-month schedule that is individually tailored to the patient has been shown to be effective. However, involuntary opioid tapering can be deleterious.45 In addition, the need for better system-oriented access to nonpharmacologic treatments for chronic pain may be particularly essential for curbing the reliance on opioid analgesics.

In addition, multifaceted interventions are needed. One institution implemented a provider-based training schedule on opioid prescribing and developed policies to reduce opioid prescribing for noncancer pain.46 After instituting opioid prescribing guidelines in an emergency department, the number of patients discharged with a prescription for opioids decreased 39.6% after the intervention and was sustained 2.5 years after the intervention.

However, larger institutions face challenges in how to provide health care providers with intervention tools and methods. The Veterans Health Administration (VHA) instituted policies for opioid prescribing and alerts within the electronic health record to try to reduce opioid prescribing. An evaluation of these measures was undertaken to determine whether they had any impact.47 For this evaluation, a total of 32.2 million new prescriptions for fentanyl, controlled-release oxycodone, and propoxyphene were written for VHA patients who met the inclusion criteria. Com-pliance with guidelines in the directives increased steadily throughout the entire study period, with no clinically meaningful inflection point near the date of each directive's release. Generalized additive modeling and interrupted time series analysis found that the indicator flag slightly improved the fit of the data, but visual inspection of the plots revealed no change at a level of practical significance. Although prescribing compliance increased throughout the period, release of FDA and VHA alerts and guidelines did not seem to contribute to this change. These findings indicate that multifaceted and sustainable system-level interventions are needed.

Specific to PLWHA populations, a social cognitive intervention was developed to target patient-level pain outcomes by providing several levels of support from peer coaches and staff interventionists.48 The intervention, Skills to Manage Pain (STOMP), is a social cognitive theory-based pain self-management intervention. STOMP consists of 12 sessions: 6 individual and 6 group sessions alternating weekly for 12 weeks. The one-on-one sessions are led by pain coaches and focus on pain education and topics of importance, including relaxation skills, sleep, physical activity, weight loss, building self-worth, and taking opioid medications. Group sessions are designed to enhance peer support related to chronic pain, with each session focused on sharing lessons learned, goals set, and challenges encountered.

A small pilot study of the intervention included participants randomized to the STOMP intervention (n = 22) or attention control group (n = 22). The study demonstrated that the intervention group had a decrease in pain from pre- to postintervention, with an average 2-point decrease on the Brief Pain Inventory total scores, and the intervention was acceptable and feasible in the clinical setting.49 The investigators also reported that the STOMP intervention was cost-effective when held to industry standards, suggesting that it could be a sustainable method for improving pain management in PLWHA.50 Additional patient, provider, and system-level interventions need to be evaluated for PLWHA, with careful attention to maintaining quality patient care, reducing pain, and improving function and quality of life.

Conclusion

Chronic pain is prevalent in PLWHA and can have a detrimental impact on physical and social functioning, adherence to disease treatment, and quality of life. Quality care for PLWHA with pain begins with a thorough assessment to address underlying causes and biopsychosocial aspects of pain for the individual. Treatments for pain, including pharmacologic and nonpharmacologic strategies, should be tailored to the patient's condition, risk for opioid abuse or addiction, and their preferences for using evidence-based nonpharmacologic strategies. System-level strategies to help curb opioid abuse and addiction may be focused at the patient, provider, and system levels. There is a dire need for more research to identify effective strategies to reduce the risk of opioid addiction while maintaining high-quality pain care among PLWHA.

References