REVIEW For reprint orders, please contact: [email protected]
The issues around opioid prescribing in HIV-related pain
Practice Points
Sarah Cox* Pain remains to be common and an important source of disability in people living with HIV (PLWH),
despite effective antiretroviral treatment. Adverse effects of opioids particularly relevant to PLWH include hypogonadism and immunosuppression. Antiretroviral medications cause drug interactions with opioids, which must be considered. Available recommendations for chronic opioid therapy for PLWH should be followed. Substance use should be screened for in PLWH before opioid therapy is commenced. While opioid prescription may be associated with additional concerns in PLWH, these need to be
balanced with the risks of undertreatment of pain. Further research into the efficacy of chronic opioid therapy in PLWH is needed, including the treatment
of HIV-related sensory neuropathy.
SUMMARY Opioids are very useful analgesics but reports of abuse, addiction and occasionally death have led to an increase in scrutiny, particularly for chronic opioid therapy. The development of effective antiretroviral therapy has changed the focus of treatment of people living with HIV from palliative care to the management of a chronic disease. It is appropriate, therefore, to review the issues around opioid prescribing in HIV in light of this and recent research, and to review the guidance available. This review briefly examines the epidemiology of pain in people living with HIV and then the use and issues around strong opioid prescribing in this group. The availability of highly active antiretroviral therapy (HAART) has changed the outlook for people living with HIV (PLWH). In the preHAART era, as a consequence of the presence of HIV and resulting immunosuppression, PLWH experienced infections, cancers and inflammatory diseases affecting all and any part of the body. Treatment of HIV and underlying diseases were often ineffective in preventing prolonged
symptomatic illness ending in death. While the search for effective treatments progressed, the focus for PLWH was on the alleviation of suffering. Pain control followed palliative care practice, with opioids being commonly used without major concern for long-term consequences in view of the short prognosis expected. Now, with the availability of HAART, the experience of HIV resembles that of a controllable
*Chelsea & Westminster Hospital NHS Foundation Trust, 369 Fulham Road, London, SW10 9NH, UK; Tel.: +44 203 315 5054; [email protected]
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Review Cox chronic illness, such as diabetes [1]. However, as with any chronic condition, there can be a significant impact of living with HIV. Drug therapy can be associated with multiple adverse effects and unpleasant symptoms, including pain. HIV predisposes to some conditions, such as non-Hodgkin’s lymphoma, even when immune function is maintained. Those who present with advanced HIV disease may still experience the illnesses associated with severe immunosuppression and even in the UK there are still hundreds of deaths from HIV each year [101]. In areas of the world where antiretroviral therapy and monitoring is less well available, the profile of HIV remains closer to that seen in the early days in the west. Opioid use in HIV is complicated by synergistic effects on the hypothalamic–pituitary–gonadal axis resulting in lowered levels of sex hormones [2]. Opioids are known to influence immune function, although the effect of this on HIV progression is unclear [3]. Drug interactions are common with anti retroviral therapy and care must be taken with the coprescription of opioids [4]. Opioid therapy is complicated by the increased incidence of substance use among PLWH and practical suggestions are made based on published guidance [5,102]. Epidemiology of pain in HIV Despite the availability of HAART, recent surveys of HIV outpatients in resource rich parts of the world suggest that pain remains a significant issue. Point prevalence rates of 34–67% have been reported, with the variance explained in part by methodological differences, but also by varying patient demographics [6,7]. Pain reported by PLWH has been described as being of moderate-to-severe intensity in 31–39% [6,8]. Pain and other symptoms have a significant impact on the quality of life of PLWH [9] and are associated with psychiatric illness, including depression, and intravenous drug use [6]. Pain in PLWH is experienced more frequently by those with a substance use history [10], those with an AIDS diagnosis and those who have attained lower educational qualifications [7]. The fact that pain remains a significant issue in PLWH with access to HAART is likely to have multiple causes. First, a significant proportion of new HIV diagnoses in resource rich countries are made in those who have already developed severe immunosuppression [11,12]. These individuals will have symptom profiles
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similar to those seen pre-HAART. Even after effective treatment is started and markers of immune function start to improve, pain persists, at least for some months [13]. Second, populations of PWLH will have higher representation from substance and intravenous drug users who are generally reported to experience more pain [10,14]. Last, pain can be an adverse effect of the antiretroviral drugs themselves, most notably as painful sensory neuropathy (SN). Where access to HAART is limited, there is evidence that pain is more prevalent. For instance, pain was reported by 83% of a multicenter symptom survey in sub-Saharan Africans living with HIV [15]. Pain in PLWH can be caused by direct effects of HIV (for instance on the peripheral nervous system), immune suppression resulting in infection or cancer, drug therapy and unrelated or indeterminate causes [16]. The sites of pain in a pre-HAART study were: headache (17%), joint pain (12%), muscle pain (12%) and polyneuropathy (10%) [16]. In a recent survey of ambulatory outpatients in New York (USA), pain was described as occurring in the legs in 9%, back in 8% and ‘all over the body’ in 2% [8]. Neuropathies are a major source of pain in HIV, particularly in the context of advanced disease. Of these, SN caused by HIV or antiretroviral therapy is the most common. Less common causes of neuropathic pain include mononeuritis multiplex occuring as a result of immunological dysfunction or coinfection with Cytomegalovirus, varicella zoster or hepatitis B or C viruses. Cytomegalovirus and varicella zoster can also cause polyradiculopathies with lumbosacral pain, saddle anesthesia and progressive flaccid paralysis. Diffuse infiltrative lymphocytosis syndrome is a distal SN or multiple mononeuropathy occurring as a hyperimmune reaction against infection with HIV [17]. PLWH are also susceptible to the neuropathies suffered by the general population, including acute zoster infections, postherpeticneuropathy, diabetic neuropathy and painful neuropathy from B12 deficiency. SN remains one the most important causes of pain in PLWH. There is a strong association between advanced HIV and SN, with a prevalence rate of 35% in one study of hospitalized patients with an AIDS diagnosis [18]. Unsuppressed HIV appears to exert a neurotoxic effect on the peripheral nerves and painful SN is a function of the severity of this damage [19]. However, a longitudinal study of over 2000 PLWH found the prevalence of peripheral neuropathy to
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The issues around opioid prescribing in HIV-related pain be 32%, despite over 80% of the cohort having their HIV well suppressed [20]. This may be, in part, explained by the fact that some antiretroviral medications are also neurotoxic, particularly the nucleoside analog reverse transcriptases stavudine, didanosine and zalcitabine. Protease inhibitors in combination with neurotoxic nucleoside analog reverse transcriptases may be associated with an increased risk of SN [20], although there is also available research that contradicts this [21]. Painful HIV SN increases with age, height and with other risk factors for peripheral neuropathy, such as diabetes [22]. HIV SN has been shown to result in significant morbidity in terms of unemployment and poorer quality of life [21]. Opioid prescribing for pain in PLWH Data from the Veterans Aging Cohort Study in the USA examined opioid prescribing for 23,651 PLWH and HIV negative-matched controls. There was a small, but statistically significant, difference in the receipt of at least one opioid prescription between groups (31 vs 28%), with PLWH being more likely to be prescribed opioids [23]. PLWH received a higher mean daily morphine equivalent dose (41 vs 37 mg) and were more likely to receive doses over the 120 mg morphine equivalent dose. In this study, PLWH were less likely than HIV-negative controls to receive opioids for longer than 90 days consecutively. By contrast, a retrospective survey of members of Kaiser Permanente healthcare plans demonstrated that rates of long-term opioid use were more than double in PLWH compared with the non-HIV infected group [24]. Prescription of long-term opioids in PLWH is positively associated with comorbidities, such as chronic hepatitis C infection, and depression, peripheral neuropathy and alcohol and drug use disorders [25–27]. Efficacy Much of the evidence for the use of opioids in HIV-related pain is extrapolated from research in non-HIV pain [26]. There is weak evidence demonstrating the short-term effectiveness of morphine [27] and transdermal fentanyl [28] in HIV-related pain. There is limited evidence for the long-term effectiveness of opioids in the general population and very little research in PLWH [5,26,29]. In a small observational study, chronic opioid therapy was not associated with a reduction in pain in PWLH [30]. The efficacy
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of opioids in HIV-related SN is as yet untested, which is of particular importance as it does not seem to respond to the drugs that are usually effective for neuropathic pain [31]. Adverse effects The common adverse effects of opioid therapy were illustrated by a meta-analysis identifying constipation (16%), nausea (15%), dizziness or vertigo (8%), drowsiness (9%), vomiting (5%), and dry or itchy skin (4%) in studies of patients with chronic noncancer pain [32]. Hyperalgesia is an important adverse effect of opioid prescription, although the incidence is unknown [33]. Serious side effects including respiratory depression and death are uncommon, but increasing, and recommendations have been produced in the USA and UK to improve safe and appropriate prescribing [5,34,102]. Opioid overdoses, including six deaths, were identified in 51 out of 9940 patients receiving opioids for chronic noncancer pain in the CONSORT study [35]. The risks of respiratory depression may be exacerbated by nonprescribed substance use. The use of opioids in PLWH is more likely to be associated with substance use, which should lead to increased caution with opioid prescribing [24]. Opioid therapy has been demonstrated to cause inhibition of the hypothalamic–pituitary–gonadal axis experimentally [36] and in patients on chronic opioid therapy [37]. PLWH are susceptible to disorders of the hypothalamic–pituitary–gonadal axis from immunological consequences of HIV infection, coinfections, particularly with Cytomegalovirus, and drugs such as steroids. While coinfections and the effects of advancing immune damage have decreased in the post-HAART era, the incidence of hypogonadism manifested by reduced testosterone remains at approximately 20% in men with HIV [2]. Chronic opioid therapy may, therefore, exacerbate the symptoms of fatigue and sexual dysfunction experienced by some PLWH. Opioids are thought to exert immuno modulating effects by their action on cytokines, phagocytes and lymphocytes [38]. In vitro studies demonstrated that T lymphocytes express opioid receptors blocked by naloxone [39]. Morphine acting on µ-opioid receptors increases the expression of HIV coreceptors on host white cells and can enhance replication of some HIV strains in animal models [3]. However, progression of HIV in intravenous drug users has been shown to be no faster than for other groups [40]. Stimulation
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Review Cox of k-opioid receptors produces an anti-inflammatory action through the downregulation of cytokines [41]. There is, as yet, no clarity about the impact of opioid drugs and chronic opioid therapy on HIV progression. Drug interactions Drug interactions are common with antiretro viral medications. Clinically significant changes in the bioavailability of opioids and antiretroviral drugs can result from their coadministration. Many of the antiretroviral drugs affect metabolic enzymes, including CYP3A and CYP2D6. Ritonavir is particularly potent in this regard and is commonly used to boost the effect of other protease inhibitors. Evidence for clinically significant interactions is often from small pharmacokinetics studies or case reports, and while theoretical effects of coadministration can be predicted, the clinical results have often not been studied. Specific antiretroviral therapy must be considered before starting any medication, including opioids. Exposure to opioids may also be affected by changes in antiretroviral medication. Advice on specific drug interactions is available from HIV pharmacists and the online HIV drug interaction resource [103]. Table 1 summarizes some of the more clinically important interactions. Buprenorphine exposure is also likely to be increased by protease inhibitors acting on CYP3A4. In a study of HIV negative volunteers on buprenorphine maintenance, boosted atazanavir (atazanavir with low-dose ritonavir) caused raised levels of buprenorphine that were associated with adverse effects in 30% [42]. Buprenorphine-maintained individuals starting protease inhibitors should be monitored for signs of opioid toxicity. The HIV drug interaction website advises halving the starting dose of buprenorphine in patients taking the protease inhibitor indinavir [103]. However, this advice is based on theoretical rather than proven effects. Close monitoring may be more appropriate to ensure neither over- or under-dosing with opioids. Coprescription of buprenorphine and tipranavir can result in a reduction of the levels of both, and careful monitoring for opioid withdrawal and antiretroviral failure is recommended [103]. Unboosted atazanavir plasma concentrations are reduced by buprenorphine and coadministration is not advised. The bioavailability of methadone is reduced by the non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs nevirapine and
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efavirenz, and withdrawal has been reported necessitating increases in methadone dose in PLWH on methadone maintenance [43–46]. By contrast, delavrudine, another NNRTI, can increase the plasma levels of methadone. Protease inhibitors reduce methadone availability with case reports of clinically significant changes in methadone levels with nelfinavir and ritonavir-boosted regimes [47,48]. Dose adjustment may be required in response to symptoms of methadone withdrawal. Cardiac arrhythmias are a risk with high-dose methadone through QT prolongation and there is a case reported of torsade de pointes after withdrawal of a lopinavir–ritonavir combination [49]. A combination of methadone and saquinavir is contraindicated in Europe owing to the cardiac risk [103]. In view of the greater risk of interactions between methadone and antiretroviral medications, alternatives such as buprenorphine may be better choices when initiating opioid therapy [50]. Fentanyl exposure can be increased by the effect of protease inhibitors on CYP3A4. Experimentally, ritonavir produced clinically significant increases in fentanyl levels. A reduced starting dose of fentanyl and careful monitoring is advised for individuals taking protease inhibitors [103,51]. Coadministration of fentanyl and saquinavir is contraindicated because of a theoretical risk of potentially fatal cardiac arrhythmias. Ritonavir can reduce the bioavailability of morphine by inducing glucuronidation, although clinically significant morphine withdrawal has not been reported. Oxycodone levels can be increased by the induction of CYP3A enzymes by protease inhibitors, especially with ritonavir containing combinations [52]. Oxycodone levels can be decreased by most of the NNRTIs that induce CYP3A4. By contrast, delavirdine is likely to increase oxycodone exposure through inhibition of CYP3A4 and CYP2D6. Coadministration of oxycodone and NNRTIs to establish whether these theoretical interactions result in clinically significant effects has not been studied. Close monitoring and appropriate dose adjustment is advised [103]. Prescribed opioid misuse, abuse, addiction & diversion Estimates of the prevalence of misuse, abuse or addiction to prescribed opioids are affected by the lack of consistent definitions in published studies. In the general population of chronic pain patients receiving chronic opioid therapy,
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The issues around opioid prescribing in HIV-related pain
Review
Table 1. Major opioid–antiretroviral drug interactions. Opioid
Antiretroviral drug
Risk
Advice
Fentanyl
Saquinavir All protease inhibitors
Contraindicated Use lower starting dose
NNRTIs
Cardiac arrhythmia Theoretical risk of toxicity from increased fentanyl availability Theoretical risk of reduced fentanyl availability
Saquinavir
Cardiac arrhythmia
Lopinavir
Methadone availability reduced by 53%
Ritonavir
Delavirdine
Methadone availability reduced when ritonavir used to boost other protease Inhibitors Methadone availability may be increased when ritonavir is used alone Methadone availability increased
Nevirapine
Methadone availability reduced by 40–60%
Rilpivarine
Rilpivarine can cause torsade de pointes and methadone can prolong the QTc interval Methadone availability reduced Methadone clearance increased
Methadone
Abacavir
Oxycodone
Codeine
Monitor and reduce dose of methadone if clinically required Opioid withdrawal has been reported Monitor and increase dose of methadone if withdrawal symptoms occur Use with caution
Saquinavir Indinavir
Buprenorphine concentrations increased Buprenorphine concentrations increased
Efavirenz Tipranavir
Buprenorphine levels decreased Both buprenorphine and tipranavir levels decreased Buprenorphine levels decreased Morphine levels reduced
Monitor and increase dose of methadone if withdrawal symptoms occur Monitor for clinical response to didanosine Monitor for clinical response to stavudine Monitor for toxicity to zidovudine Do not coprescribe Monitor for toxicity to buprenorphine and reduce if indicated Consider dose reduction in buprenorphine Consider dose reduction in buprenorphine when starting indinavir Monitor for withdrawal Monitor for response to tipranavir and opioid withdrawal Monitor for withdrawal Monitor analgesic effect of morphine
Oxycodone levels increased Oxycodone levels decreased
Monitor for adverse effects of oxycodone Monitor for analgesic effect of oxycodone
Ritonavir inhibits CYP2D6 and could reduce conversion of codeine to morphine Theoretical risk of reduction in availability of active metabolite
Monitor analgesic effect of codeine
Didanosine (ddI) Stavudine (d4T) Zidovudine (AZT) Buprenorphine Atazanavir Atazanavir/ritonavir
Morphine
Monitor and adjust dose of fentanyl if clinically required Contraindicated in Europe; caution advised in the USA Monitor and increase dose of methadone if withdrawal symptoms occur Monitor and adjust dose of methadone as appropriate
Etravirine Ritonavir and ritonavir/protease inhibitor combinations Protease inhibitors NNRTIs (except delavirdine) Ritonavir NNRTIs
Methadone decreases didanosine concentrations Methadone decreases stavudine concentrations Methadone increases zidovudine concentrations Atazanavir levels reduced by buprenorphine Buprenorphine concentrations increased
Monitor analgesic effect of codeine
NNRTI: Non-nucleoside reverse transcriptase inhibitor; QTc: Corrected QT. Data taken from [103].
the incidence of aberrant drug-related behaviors was 11.5% in a structured review of the evidence [53]. The rate of abuse or addiction was calculated to be 3.27%, falling to 0.19% in those
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patients preselected for no previous or current history of abuse or addiction. A large prospective study of members of two healthcare providers revealed levels of possible abuse of prescription
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Review Cox opioids in 20–24% and probable abuse in 3–6% [54]. Of 109 people entering a drug treatment program for oxycodone addiction, 51 (47%) reported they had first been exposed to opioids through a prescription for pain, although 31% of this group had a prior history of problem use of alcohol or other substances [55]. The most powerful predictors of misuse, abuse or addiction with chronic opioid therapy are a personal or family history of alcohol or drug abuse [5]. Limited available research in PLWH demonstrates widely variable rates of abuse of or addiction to prescribed opioids. Nonmedical use of prescription opioids has been reported by 13% of US military veterans living with HIV [56]. In a survey of homeless PLWH, 37% had a history of aberrant opioid behaviour within the previous 90 days [57]. In this study, selling opioid analgesia was one of the major aberrant behaviors described by 44% of the sample over their lifetime. Diversion of prescription opioids puts the general population at risk of serious adverse effects, including death. Illicit substance use was diagnosed by structured interview or urine toxicology in 62% of PLWH receiving prescription opioids [58]. In PLWH, aberrant use of prescription opioids was strongly predicted by a history of problem drug use in a nationally representative sample in the USA [59]. Data from the National Survey on Drug Use and Health in the USA reveals that over 80% of PLWH had a lifetime history of illicit drug use and a third had used an illicit drug in the last month [104]. Additionally, over a quarter had engaged in binge drinking in the last month. Almost a quarter of PLWH were in need of alcohol or illicit drug use treatment in the past year. However, substance use has also been associated with increased pain in PLWH [10,14] and a prohibition of use of opioids in this group may result in undertreatment of pain. Some evidence exists that pain in HIV is more likely to be undertreated than cancer pain [60,61]. In the preHAAAT era, PLWH who had a history of injection drug use received less analgesia than other PLWH despite having equivalent pretreatment pain intensity ratings [62]. Pain is associated with significant physical and psychological morbidity in PLWH [9]. Consequences of undertreatment of pain may also include reduced adherence to HIV management [63]. Pain predicted nonattendance for HIV review in PLWH and substance use [64]. In addition, a survey of attitudes and behaviors demonstrated that undertreatment of pain would
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encourage PLWH to consider major aberrant behaviors such as the use of street drugs [65]. Recommendations are available from the American Pain Society/American Academy of Pain Management guidelines and British Pain Society for the management of chronic opioid therapy in noncancer pain based mainly on benefit and harm assessments as the evidence is mostly low quality [5]. There is concern that these guidelines are not being followed in PLWH [25,66]. Furthermore, community and HIV physicians may have low confidence and success in accurately identifying prescription opioid misuse [66,67]. Some PLWH will have been started on opioid therapy when very ill, with consequences of advanced immunosuppression. Others will have commenced opioids use outside specialist pain management services. These patients may not have had opioid treatment started according to the guidance now available [5,102]. If chronic opioid therapy is being considered or for those referred and already taking strong opioids, it is appropriate to do a full formal assessment. Clarity of diagnosis, prior trials of nonopioid pain relief methods and an assessment of risks, including screening for substance use and mental health problems, should be carried out. A clear explanation should be given of the reasons why chronic opioid therapy is not recommended as a first-line analgesic regime. Specific concerns about hypogonadism and hyperalgesia, together with the potential for immunological effects, need to be raised with PLWH. The discussion should include an agreement of the aims of treatment and goals, which may include a reduction in opioid dose or opioid switch to exclude hyperalgesia, or a plan to try alternative analgesics and wean off opioids with support if therapeutic goals are not being met. Individuals receiving chronic opioid therapy should have an identified clinician responsible for their care who accepts responsibility for coordinating consultation and communication. Aberrant behaviors should prompt reevaluation of the appropriateness of chronic opioid therapy. Referral to addiction services should be offered for those with problem substance use. Where substance use has been identified, joint management by specialists in pain management and substance misuse is strongly recommended. Conclusion & future perspective Pain is an important cause of morbidity in PLWH despite disease management with HAART. While there are other options for analgesia, this
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The issues around opioid prescribing in HIV-related pain review deals solely with the issues around opioid prescribing in HIV-related pain. There are important differences in the etiology of pain in PLWH, in particular with the significant and continued high prevalence of HIV SN. PLWH are more likely to have prior or current issues with substance misuse and this suggests a need for closer adherence to available guidance for safe prescribing [6,7]. This review has identified areas where more evidence is needed, these include: The efficacy of chronic opioid therapy gener-
ally and for PLWH specifically. There is at present low-quality evidence for chronic opioid prescribing generally and more evidence in this area would be helpful in guiding those treating chronic pain in PLWH; The efficacy of opioids in HIV SN. This condi-
tion causes significant distress for individuals despite adherence to HIV combination therapy. The available drug therapies are of limited efficacy and the place for opioids is currently unclear. Research in this area is complicated by a lack of funding; however, this question remains an important one for clinicians and PLWH; References n
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Interaction between buprenorphine and atazanavir or atazanavir/ritonavir. Drug Alcohol Depend. 91(2–3), 269–278 (2007). 43 Otero M, Fuertes A, Sanchez R et al.
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NJ. Methadone-induced torsade de pointes after stopping lopinavir-ritonavir. Eur. J. Clin. Microbiol. Infect. Dis. 26(5), 367–379 (2007). 50 McCance-Katz EF, Sullivan LS, Nallani S.
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The issues around opioid prescribing in HIV-related pain
Practice Points
Sarah Cox* Pain remains to be common and an important source of disability in people living with HIV (PLWH),
despite effective antiretroviral treatment. Adverse effects of opioids particularly relevant to PLWH include hypogonadism and immunosuppression. Antiretroviral medications cause drug interactions with opioids, which must be considered. Available recommendations for chronic opioid therapy for PLWH should be followed. Substance use should be screened for in PLWH before opioid therapy is commenced. While opioid prescription may be associated with additional concerns in PLWH, these need to be
balanced with the risks of undertreatment of pain. Further research into the efficacy of chronic opioid therapy in PLWH is needed, including the treatment
of HIV-related sensory neuropathy.
SUMMARY Opioids are very useful analgesics but reports of abuse, addiction and occasionally death have led to an increase in scrutiny, particularly for chronic opioid therapy. The development of effective antiretroviral therapy has changed the focus of treatment of people living with HIV from palliative care to the management of a chronic disease. It is appropriate, therefore, to review the issues around opioid prescribing in HIV in light of this and recent research, and to review the guidance available. This review briefly examines the epidemiology of pain in people living with HIV and then the use and issues around strong opioid prescribing in this group. The availability of highly active antiretroviral therapy (HAART) has changed the outlook for people living with HIV (PLWH). In the preHAART era, as a consequence of the presence of HIV and resulting immunosuppression, PLWH experienced infections, cancers and inflammatory diseases affecting all and any part of the body. Treatment of HIV and underlying diseases were often ineffective in preventing prolonged
symptomatic illness ending in death. While the search for effective treatments progressed, the focus for PLWH was on the alleviation of suffering. Pain control followed palliative care practice, with opioids being commonly used without major concern for long-term consequences in view of the short prognosis expected. Now, with the availability of HAART, the experience of HIV resembles that of a controllable
*Chelsea & Westminster Hospital NHS Foundation Trust, 369 Fulham Road, London, SW10 9NH, UK; Tel.: +44 203 315 5054; [email protected]
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Review Cox chronic illness, such as diabetes [1]. However, as with any chronic condition, there can be a significant impact of living with HIV. Drug therapy can be associated with multiple adverse effects and unpleasant symptoms, including pain. HIV predisposes to some conditions, such as non-Hodgkin’s lymphoma, even when immune function is maintained. Those who present with advanced HIV disease may still experience the illnesses associated with severe immunosuppression and even in the UK there are still hundreds of deaths from HIV each year [101]. In areas of the world where antiretroviral therapy and monitoring is less well available, the profile of HIV remains closer to that seen in the early days in the west. Opioid use in HIV is complicated by synergistic effects on the hypothalamic–pituitary–gonadal axis resulting in lowered levels of sex hormones [2]. Opioids are known to influence immune function, although the effect of this on HIV progression is unclear [3]. Drug interactions are common with anti retroviral therapy and care must be taken with the coprescription of opioids [4]. Opioid therapy is complicated by the increased incidence of substance use among PLWH and practical suggestions are made based on published guidance [5,102]. Epidemiology of pain in HIV Despite the availability of HAART, recent surveys of HIV outpatients in resource rich parts of the world suggest that pain remains a significant issue. Point prevalence rates of 34–67% have been reported, with the variance explained in part by methodological differences, but also by varying patient demographics [6,7]. Pain reported by PLWH has been described as being of moderate-to-severe intensity in 31–39% [6,8]. Pain and other symptoms have a significant impact on the quality of life of PLWH [9] and are associated with psychiatric illness, including depression, and intravenous drug use [6]. Pain in PLWH is experienced more frequently by those with a substance use history [10], those with an AIDS diagnosis and those who have attained lower educational qualifications [7]. The fact that pain remains a significant issue in PLWH with access to HAART is likely to have multiple causes. First, a significant proportion of new HIV diagnoses in resource rich countries are made in those who have already developed severe immunosuppression [11,12]. These individuals will have symptom profiles
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similar to those seen pre-HAART. Even after effective treatment is started and markers of immune function start to improve, pain persists, at least for some months [13]. Second, populations of PWLH will have higher representation from substance and intravenous drug users who are generally reported to experience more pain [10,14]. Last, pain can be an adverse effect of the antiretroviral drugs themselves, most notably as painful sensory neuropathy (SN). Where access to HAART is limited, there is evidence that pain is more prevalent. For instance, pain was reported by 83% of a multicenter symptom survey in sub-Saharan Africans living with HIV [15]. Pain in PLWH can be caused by direct effects of HIV (for instance on the peripheral nervous system), immune suppression resulting in infection or cancer, drug therapy and unrelated or indeterminate causes [16]. The sites of pain in a pre-HAART study were: headache (17%), joint pain (12%), muscle pain (12%) and polyneuropathy (10%) [16]. In a recent survey of ambulatory outpatients in New York (USA), pain was described as occurring in the legs in 9%, back in 8% and ‘all over the body’ in 2% [8]. Neuropathies are a major source of pain in HIV, particularly in the context of advanced disease. Of these, SN caused by HIV or antiretroviral therapy is the most common. Less common causes of neuropathic pain include mononeuritis multiplex occuring as a result of immunological dysfunction or coinfection with Cytomegalovirus, varicella zoster or hepatitis B or C viruses. Cytomegalovirus and varicella zoster can also cause polyradiculopathies with lumbosacral pain, saddle anesthesia and progressive flaccid paralysis. Diffuse infiltrative lymphocytosis syndrome is a distal SN or multiple mononeuropathy occurring as a hyperimmune reaction against infection with HIV [17]. PLWH are also susceptible to the neuropathies suffered by the general population, including acute zoster infections, postherpeticneuropathy, diabetic neuropathy and painful neuropathy from B12 deficiency. SN remains one the most important causes of pain in PLWH. There is a strong association between advanced HIV and SN, with a prevalence rate of 35% in one study of hospitalized patients with an AIDS diagnosis [18]. Unsuppressed HIV appears to exert a neurotoxic effect on the peripheral nerves and painful SN is a function of the severity of this damage [19]. However, a longitudinal study of over 2000 PLWH found the prevalence of peripheral neuropathy to
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The issues around opioid prescribing in HIV-related pain be 32%, despite over 80% of the cohort having their HIV well suppressed [20]. This may be, in part, explained by the fact that some antiretroviral medications are also neurotoxic, particularly the nucleoside analog reverse transcriptases stavudine, didanosine and zalcitabine. Protease inhibitors in combination with neurotoxic nucleoside analog reverse transcriptases may be associated with an increased risk of SN [20], although there is also available research that contradicts this [21]. Painful HIV SN increases with age, height and with other risk factors for peripheral neuropathy, such as diabetes [22]. HIV SN has been shown to result in significant morbidity in terms of unemployment and poorer quality of life [21]. Opioid prescribing for pain in PLWH Data from the Veterans Aging Cohort Study in the USA examined opioid prescribing for 23,651 PLWH and HIV negative-matched controls. There was a small, but statistically significant, difference in the receipt of at least one opioid prescription between groups (31 vs 28%), with PLWH being more likely to be prescribed opioids [23]. PLWH received a higher mean daily morphine equivalent dose (41 vs 37 mg) and were more likely to receive doses over the 120 mg morphine equivalent dose. In this study, PLWH were less likely than HIV-negative controls to receive opioids for longer than 90 days consecutively. By contrast, a retrospective survey of members of Kaiser Permanente healthcare plans demonstrated that rates of long-term opioid use were more than double in PLWH compared with the non-HIV infected group [24]. Prescription of long-term opioids in PLWH is positively associated with comorbidities, such as chronic hepatitis C infection, and depression, peripheral neuropathy and alcohol and drug use disorders [25–27]. Efficacy Much of the evidence for the use of opioids in HIV-related pain is extrapolated from research in non-HIV pain [26]. There is weak evidence demonstrating the short-term effectiveness of morphine [27] and transdermal fentanyl [28] in HIV-related pain. There is limited evidence for the long-term effectiveness of opioids in the general population and very little research in PLWH [5,26,29]. In a small observational study, chronic opioid therapy was not associated with a reduction in pain in PWLH [30]. The efficacy
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of opioids in HIV-related SN is as yet untested, which is of particular importance as it does not seem to respond to the drugs that are usually effective for neuropathic pain [31]. Adverse effects The common adverse effects of opioid therapy were illustrated by a meta-analysis identifying constipation (16%), nausea (15%), dizziness or vertigo (8%), drowsiness (9%), vomiting (5%), and dry or itchy skin (4%) in studies of patients with chronic noncancer pain [32]. Hyperalgesia is an important adverse effect of opioid prescription, although the incidence is unknown [33]. Serious side effects including respiratory depression and death are uncommon, but increasing, and recommendations have been produced in the USA and UK to improve safe and appropriate prescribing [5,34,102]. Opioid overdoses, including six deaths, were identified in 51 out of 9940 patients receiving opioids for chronic noncancer pain in the CONSORT study [35]. The risks of respiratory depression may be exacerbated by nonprescribed substance use. The use of opioids in PLWH is more likely to be associated with substance use, which should lead to increased caution with opioid prescribing [24]. Opioid therapy has been demonstrated to cause inhibition of the hypothalamic–pituitary–gonadal axis experimentally [36] and in patients on chronic opioid therapy [37]. PLWH are susceptible to disorders of the hypothalamic–pituitary–gonadal axis from immunological consequences of HIV infection, coinfections, particularly with Cytomegalovirus, and drugs such as steroids. While coinfections and the effects of advancing immune damage have decreased in the post-HAART era, the incidence of hypogonadism manifested by reduced testosterone remains at approximately 20% in men with HIV [2]. Chronic opioid therapy may, therefore, exacerbate the symptoms of fatigue and sexual dysfunction experienced by some PLWH. Opioids are thought to exert immuno modulating effects by their action on cytokines, phagocytes and lymphocytes [38]. In vitro studies demonstrated that T lymphocytes express opioid receptors blocked by naloxone [39]. Morphine acting on µ-opioid receptors increases the expression of HIV coreceptors on host white cells and can enhance replication of some HIV strains in animal models [3]. However, progression of HIV in intravenous drug users has been shown to be no faster than for other groups [40]. Stimulation
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Review Cox of k-opioid receptors produces an anti-inflammatory action through the downregulation of cytokines [41]. There is, as yet, no clarity about the impact of opioid drugs and chronic opioid therapy on HIV progression. Drug interactions Drug interactions are common with antiretro viral medications. Clinically significant changes in the bioavailability of opioids and antiretroviral drugs can result from their coadministration. Many of the antiretroviral drugs affect metabolic enzymes, including CYP3A and CYP2D6. Ritonavir is particularly potent in this regard and is commonly used to boost the effect of other protease inhibitors. Evidence for clinically significant interactions is often from small pharmacokinetics studies or case reports, and while theoretical effects of coadministration can be predicted, the clinical results have often not been studied. Specific antiretroviral therapy must be considered before starting any medication, including opioids. Exposure to opioids may also be affected by changes in antiretroviral medication. Advice on specific drug interactions is available from HIV pharmacists and the online HIV drug interaction resource [103]. Table 1 summarizes some of the more clinically important interactions. Buprenorphine exposure is also likely to be increased by protease inhibitors acting on CYP3A4. In a study of HIV negative volunteers on buprenorphine maintenance, boosted atazanavir (atazanavir with low-dose ritonavir) caused raised levels of buprenorphine that were associated with adverse effects in 30% [42]. Buprenorphine-maintained individuals starting protease inhibitors should be monitored for signs of opioid toxicity. The HIV drug interaction website advises halving the starting dose of buprenorphine in patients taking the protease inhibitor indinavir [103]. However, this advice is based on theoretical rather than proven effects. Close monitoring may be more appropriate to ensure neither over- or under-dosing with opioids. Coprescription of buprenorphine and tipranavir can result in a reduction of the levels of both, and careful monitoring for opioid withdrawal and antiretroviral failure is recommended [103]. Unboosted atazanavir plasma concentrations are reduced by buprenorphine and coadministration is not advised. The bioavailability of methadone is reduced by the non-nucleoside reverse transcriptase inhibitor (NNRTI) drugs nevirapine and
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efavirenz, and withdrawal has been reported necessitating increases in methadone dose in PLWH on methadone maintenance [43–46]. By contrast, delavrudine, another NNRTI, can increase the plasma levels of methadone. Protease inhibitors reduce methadone availability with case reports of clinically significant changes in methadone levels with nelfinavir and ritonavir-boosted regimes [47,48]. Dose adjustment may be required in response to symptoms of methadone withdrawal. Cardiac arrhythmias are a risk with high-dose methadone through QT prolongation and there is a case reported of torsade de pointes after withdrawal of a lopinavir–ritonavir combination [49]. A combination of methadone and saquinavir is contraindicated in Europe owing to the cardiac risk [103]. In view of the greater risk of interactions between methadone and antiretroviral medications, alternatives such as buprenorphine may be better choices when initiating opioid therapy [50]. Fentanyl exposure can be increased by the effect of protease inhibitors on CYP3A4. Experimentally, ritonavir produced clinically significant increases in fentanyl levels. A reduced starting dose of fentanyl and careful monitoring is advised for individuals taking protease inhibitors [103,51]. Coadministration of fentanyl and saquinavir is contraindicated because of a theoretical risk of potentially fatal cardiac arrhythmias. Ritonavir can reduce the bioavailability of morphine by inducing glucuronidation, although clinically significant morphine withdrawal has not been reported. Oxycodone levels can be increased by the induction of CYP3A enzymes by protease inhibitors, especially with ritonavir containing combinations [52]. Oxycodone levels can be decreased by most of the NNRTIs that induce CYP3A4. By contrast, delavirdine is likely to increase oxycodone exposure through inhibition of CYP3A4 and CYP2D6. Coadministration of oxycodone and NNRTIs to establish whether these theoretical interactions result in clinically significant effects has not been studied. Close monitoring and appropriate dose adjustment is advised [103]. Prescribed opioid misuse, abuse, addiction & diversion Estimates of the prevalence of misuse, abuse or addiction to prescribed opioids are affected by the lack of consistent definitions in published studies. In the general population of chronic pain patients receiving chronic opioid therapy,
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The issues around opioid prescribing in HIV-related pain
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Table 1. Major opioid–antiretroviral drug interactions. Opioid
Antiretroviral drug
Risk
Advice
Fentanyl
Saquinavir All protease inhibitors
Contraindicated Use lower starting dose
NNRTIs
Cardiac arrhythmia Theoretical risk of toxicity from increased fentanyl availability Theoretical risk of reduced fentanyl availability
Saquinavir
Cardiac arrhythmia
Lopinavir
Methadone availability reduced by 53%
Ritonavir
Delavirdine
Methadone availability reduced when ritonavir used to boost other protease Inhibitors Methadone availability may be increased when ritonavir is used alone Methadone availability increased
Nevirapine
Methadone availability reduced by 40–60%
Rilpivarine
Rilpivarine can cause torsade de pointes and methadone can prolong the QTc interval Methadone availability reduced Methadone clearance increased
Methadone
Abacavir
Oxycodone
Codeine
Monitor and reduce dose of methadone if clinically required Opioid withdrawal has been reported Monitor and increase dose of methadone if withdrawal symptoms occur Use with caution
Saquinavir Indinavir
Buprenorphine concentrations increased Buprenorphine concentrations increased
Efavirenz Tipranavir
Buprenorphine levels decreased Both buprenorphine and tipranavir levels decreased Buprenorphine levels decreased Morphine levels reduced
Monitor and increase dose of methadone if withdrawal symptoms occur Monitor for clinical response to didanosine Monitor for clinical response to stavudine Monitor for toxicity to zidovudine Do not coprescribe Monitor for toxicity to buprenorphine and reduce if indicated Consider dose reduction in buprenorphine Consider dose reduction in buprenorphine when starting indinavir Monitor for withdrawal Monitor for response to tipranavir and opioid withdrawal Monitor for withdrawal Monitor analgesic effect of morphine
Oxycodone levels increased Oxycodone levels decreased
Monitor for adverse effects of oxycodone Monitor for analgesic effect of oxycodone
Ritonavir inhibits CYP2D6 and could reduce conversion of codeine to morphine Theoretical risk of reduction in availability of active metabolite
Monitor analgesic effect of codeine
Didanosine (ddI) Stavudine (d4T) Zidovudine (AZT) Buprenorphine Atazanavir Atazanavir/ritonavir
Morphine
Monitor and adjust dose of fentanyl if clinically required Contraindicated in Europe; caution advised in the USA Monitor and increase dose of methadone if withdrawal symptoms occur Monitor and adjust dose of methadone as appropriate
Etravirine Ritonavir and ritonavir/protease inhibitor combinations Protease inhibitors NNRTIs (except delavirdine) Ritonavir NNRTIs
Methadone decreases didanosine concentrations Methadone decreases stavudine concentrations Methadone increases zidovudine concentrations Atazanavir levels reduced by buprenorphine Buprenorphine concentrations increased
Monitor analgesic effect of codeine
NNRTI: Non-nucleoside reverse transcriptase inhibitor; QTc: Corrected QT. Data taken from [103].
the incidence of aberrant drug-related behaviors was 11.5% in a structured review of the evidence [53]. The rate of abuse or addiction was calculated to be 3.27%, falling to 0.19% in those
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patients preselected for no previous or current history of abuse or addiction. A large prospective study of members of two healthcare providers revealed levels of possible abuse of prescription
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Review Cox opioids in 20–24% and probable abuse in 3–6% [54]. Of 109 people entering a drug treatment program for oxycodone addiction, 51 (47%) reported they had first been exposed to opioids through a prescription for pain, although 31% of this group had a prior history of problem use of alcohol or other substances [55]. The most powerful predictors of misuse, abuse or addiction with chronic opioid therapy are a personal or family history of alcohol or drug abuse [5]. Limited available research in PLWH demonstrates widely variable rates of abuse of or addiction to prescribed opioids. Nonmedical use of prescription opioids has been reported by 13% of US military veterans living with HIV [56]. In a survey of homeless PLWH, 37% had a history of aberrant opioid behaviour within the previous 90 days [57]. In this study, selling opioid analgesia was one of the major aberrant behaviors described by 44% of the sample over their lifetime. Diversion of prescription opioids puts the general population at risk of serious adverse effects, including death. Illicit substance use was diagnosed by structured interview or urine toxicology in 62% of PLWH receiving prescription opioids [58]. In PLWH, aberrant use of prescription opioids was strongly predicted by a history of problem drug use in a nationally representative sample in the USA [59]. Data from the National Survey on Drug Use and Health in the USA reveals that over 80% of PLWH had a lifetime history of illicit drug use and a third had used an illicit drug in the last month [104]. Additionally, over a quarter had engaged in binge drinking in the last month. Almost a quarter of PLWH were in need of alcohol or illicit drug use treatment in the past year. However, substance use has also been associated with increased pain in PLWH [10,14] and a prohibition of use of opioids in this group may result in undertreatment of pain. Some evidence exists that pain in HIV is more likely to be undertreated than cancer pain [60,61]. In the preHAAAT era, PLWH who had a history of injection drug use received less analgesia than other PLWH despite having equivalent pretreatment pain intensity ratings [62]. Pain is associated with significant physical and psychological morbidity in PLWH [9]. Consequences of undertreatment of pain may also include reduced adherence to HIV management [63]. Pain predicted nonattendance for HIV review in PLWH and substance use [64]. In addition, a survey of attitudes and behaviors demonstrated that undertreatment of pain would
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encourage PLWH to consider major aberrant behaviors such as the use of street drugs [65]. Recommendations are available from the American Pain Society/American Academy of Pain Management guidelines and British Pain Society for the management of chronic opioid therapy in noncancer pain based mainly on benefit and harm assessments as the evidence is mostly low quality [5]. There is concern that these guidelines are not being followed in PLWH [25,66]. Furthermore, community and HIV physicians may have low confidence and success in accurately identifying prescription opioid misuse [66,67]. Some PLWH will have been started on opioid therapy when very ill, with consequences of advanced immunosuppression. Others will have commenced opioids use outside specialist pain management services. These patients may not have had opioid treatment started according to the guidance now available [5,102]. If chronic opioid therapy is being considered or for those referred and already taking strong opioids, it is appropriate to do a full formal assessment. Clarity of diagnosis, prior trials of nonopioid pain relief methods and an assessment of risks, including screening for substance use and mental health problems, should be carried out. A clear explanation should be given of the reasons why chronic opioid therapy is not recommended as a first-line analgesic regime. Specific concerns about hypogonadism and hyperalgesia, together with the potential for immunological effects, need to be raised with PLWH. The discussion should include an agreement of the aims of treatment and goals, which may include a reduction in opioid dose or opioid switch to exclude hyperalgesia, or a plan to try alternative analgesics and wean off opioids with support if therapeutic goals are not being met. Individuals receiving chronic opioid therapy should have an identified clinician responsible for their care who accepts responsibility for coordinating consultation and communication. Aberrant behaviors should prompt reevaluation of the appropriateness of chronic opioid therapy. Referral to addiction services should be offered for those with problem substance use. Where substance use has been identified, joint management by specialists in pain management and substance misuse is strongly recommended. Conclusion & future perspective Pain is an important cause of morbidity in PLWH despite disease management with HAART. While there are other options for analgesia, this
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The issues around opioid prescribing in HIV-related pain review deals solely with the issues around opioid prescribing in HIV-related pain. There are important differences in the etiology of pain in PLWH, in particular with the significant and continued high prevalence of HIV SN. PLWH are more likely to have prior or current issues with substance misuse and this suggests a need for closer adherence to available guidance for safe prescribing [6,7]. This review has identified areas where more evidence is needed, these include: The efficacy of chronic opioid therapy gener-
ally and for PLWH specifically. There is at present low-quality evidence for chronic opioid prescribing generally and more evidence in this area would be helpful in guiding those treating chronic pain in PLWH; The efficacy of opioids in HIV SN. This condi-
tion causes significant distress for individuals despite adherence to HIV combination therapy. The available drug therapies are of limited efficacy and the place for opioids is currently unclear. Research in this area is complicated by a lack of funding; however, this question remains an important one for clinicians and PLWH; References n
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specific antiretroviral drugs are poorly characterized. Interactions are complex and not always borne out by predictions from a knowledge of the pharmacology. Interactions with combinations of antiretroviral drugs and specific opioids need further research to understand; Adverse effects of opioids in the general popula-
tion are reasonably well understood. However, the effect of chronic opioid therapy on disease progression in HIV is still unclear. In addition, further work is needed on the effects of chronic opioid therapy on the h ypothalamic–gonadal axis. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Medicine Opioids Guidelines Panel. Opioid treatment guidelines: Clinical Guidelines for the use of chronic opioid therapy in chronic noncancer pain. J. Pain 10(2), 113–130 (2009).
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