Chronic noncancer pain (CNCP) is often managed with a combination of interventional therapies and pharmacological modalities, including opioid and nonopioid medications. Whereas opioids have proven effective for the treatment of acute pain, there is insufficient evidence that chronic use results in sustained pain relief, increased function, or improved quality of life with outcomes measured at 1 year or even 6 weeks.1 The ambiguous benefits of chronic opioid therapy (COT) are outweighed by the potential harms in many patients, to include opioid use disorder, overdose, myocardial infarction, and an increased risk of motor vehicle collision.2 Evidence also suggests that the benefits of nonpharmacological and nonopioid pharmacological therapy may be greater than or equal to COT, but with a decreased risk of harm.3
The long-term efficacy of many interventional pain procedures for treatment of chronic pain has not been fully established due to heterogeneity in the literature. Nonstandardized treatments used for dissimilar pathologies and variable outcome measures precludes consequential meta-analyses of published material and leads to the questionable conclusion that such procedures are minimally effective as therapeutic options.4 Similar response rates to both active and placebo injections further complicate interpretation of the data. Published reductions in opioid use after interventional pain procedures are generally poorly quantified or often not reported at all. Some randomized trials evaluating procedural interventions have excluded patients on moderate- or high-dose opioids,5 because previous studies have shown that individuals on opioids, or who are receiving higher opioid dosages for cancer pain, are more likely to fail certain procedures such as epidural steroid injections (ESIs),6 cervical facet joint denervation,7 spine surgery,8 celiac plexus neurolysis,9 and possibly sacroiliac joint radiofrequency denervation.10 Studies demonstrating consistent reductions in pain and opioid use will likely incorporate interventional pain treatments as part of a multimodal approach rather than stand-alone therapy, making their isolated contribution difficult to detect.
In the setting of efforts to decrease opioid use for CNCP, interventional therapies will become an important strategy to manage chronic pain patients. Many studies evaluating interventional pain procedures use opioid reduction as a secondary end point,11 although no study has been specifically designed and powered to detect a difference in opioid use over time. Successful reduction of pain or increases in functionality may allow for concurrent decreases in the need for pain medications such as opioids. The purpose of this review is to consider whether use of commonly performed interventional pain procedures may change opioid use patterns in CNCP patients. The focus of this article is on the most frequently performed interventional pain procedures, including ESIs, spinal cord stimulators, and facet joint radiofrequency ablations (RFAs).
Standard search engines and cross-referenced citations identified the literature basis for the updated material contained within this review. MEDLINE was searched from 1997 forward to identify new material by using MeSH terms and text words as individual headings or in relevant combinations: “epidural,” “steroid injection,” “transforaminal,” “interlaminar,” “caudal,” “facet joint,” “RFA,” “neurotomy,” “facet joint injection,” “zygapophyseal joint injection,” “RFA,” “pulsed RFA,” “sacroiliac joint,” “intra-articular facet joint injection,” “sacroiliac joint injection,” “spinal cord stimulation (SCS),” “opioid use,” “opioid reduction,” and “analgesic reduction.” Details of the search are provided in Supplemental Digital Content, Appendix 1, http://links.lww.com/AA/B891. Searches encompassed all randomized trials published from 1997 to the present. Non-human studies, conference abstracts, and nonrandomized trials were excluded. Articles that did not report changes in medication usage associated with an interventional pain procedure were excluded. Additionally, studies in which opioid use was an exclusion criterion were also not included. When suitable articles were found, references were iteratively searched for additional relevant citations that were not identified in the database search.
In this review, the primary outcome sought was the reduction of opioid analgesics at any point in time following an interventional pain procedure. The data are summarized in the Table.
ESIs and Radiofrequency Treatment for Radicular Pain
Transforaminal, interlaminar, and caudal epidural steroids injections are beneficial in the treatment of radicular pain emanating from a lumbar herniated intervertebral disc.11,26 Comparison of pre- to postepidural data within the same treatment group indicates that opioid use is decreased after ESIs in the setting of a lumbar herniated disc for at least the first 3 months.12,13 One 3-arm, multicenter randomized controlled trial (RCT) performed in 84 subjects demonstrated decreased analgesic use among subjects receiving an ESI compared to before the intervention at 6 months, but the difference between groups fell shy of statistical significance, and opioid use was not separated from nonopioid analgesics.14 This is potentially due to the natural history of radiculopathy, in which most patients’ pain decreases over time, obfuscating the need for COT. An RCT of 113 subjects allowing subjects to receive repeat ESIs as needed did not observe a decreased need for continued opioid therapy at 6 months.15
Even less encouraging is the opioid reduction observed after ESIs for other conditions such as discogenic pain, post–spine surgery pain, or spinal stenosis. Randomized trials performed for chronic axial back pain, postsurgical pain, and spinal stenosis have found that opioid consumption after epidural injections was significantly reduced after both local anesthetic alone and local anesthetic with steroid.27–34
However, comparison between treatment groups of opioid use before and after the procedure did not demonstrate any differences. This could reflect that opioid reduction during the study period is an inappropriate outcome, that local anesthetic epidural injections are not a truly inert placebo, or that monotherapy with ESIs are truly not sufficient to meaningfully reduce opioid use. These consistent findings are from the same group of authors, raising the possibility of recurring methodological shortcomings. Two RCTs that included subjects with both herniated disks and spinal stenosis failed to demonstrate a decrease in pain scores or opioid consumption at 4 weeks or 3 months.35,36 RFA of the affected dorsal root ganglia at 67°C was not shown to be more effective than a sham procedure in reducing opioid use in an RCT evaluating 80 subjects with chronic radicular pain.16
Facet Joint Injections and RFA
RFA of the zygapophyseal or facet joint is frequently performed for the treatment of axial spine pain. Three RCTs with a total of 158 subjects evaluating ablation of the medial branches of the posterior ramus innervating the painful facet joints, as determined by diagnostic injections, resulted in long-lasting reduction in pain and overall analgesic consumption when measured between 1 month and 2 years.17–19 An RCT performed in 60 subjects receiving RFA, pulsed radiofrequency neuromodulation, or sham ablation resulted in a greater reduction in analgesic use at 1 year in subjects treated with RFA compared to pulsed radiofrequency, which in turn was associated with a greater decrease in pain medications than those in the placebo group, but opioid use was not separated out from nonopioid consumption.20 An RCT conducted in 56 subjects comparing medial branch RFA to intra-articular facet steroid injection did not result in differences in analgesic pain medication use at 6 months, although opioid use was not specifically examined.21 Comparison of RFA to a sham procedure in an RCT containing 80 subjects failed to produce any decrease in analgesic use after a brief 3-month follow-up period.22 No RCTs evaluating intra-articular facet joint steroids injections to placebo were found to report on opioid consumption after the procedure, but intra-articular facet steroid injections have been shown in evidence-based reviews to be ineffective compared to control injections for pain relief and other outcome measures.37,38
Sacroiliac Joint Injections and RFAs
No trials evaluating steroid injections for treatment of sacroiliac joint pain reported changes in opioid consumption. An RCT evaluating radiofrequency denervation in 28 subjects with sacroiliac joint pain found that the treatment group was able to reduce analgesic medications, including opioids, at a significantly greater rate (77% vs 8% at 1 month) than those who received placebo through the 6-month follow-up.23 Medication reduction was defined in this study as cessation of a nonopioid analgesic and/or a ≥20% reduction in opioid consumption. Although opioid use was not examined separately, 46% of participants were receiving baseline opioid medications.
Spinal Cord Stimulation
SCS involves the use of permanently implanted electrodes in the dorsal epidural space to treat extremity and sometimes spinal or visceral pain. An RCT evaluating 100 subjects using SCS in the setting of failed back surgery syndrome demonstrated a nonsignificant trend toward decreased opioid consumption at 6 months compared to conventional medical management.24 In the same study, 8 subjects in the SCS group were able to cease opioid use compared to 1 in the medical management group. An RCT comparing high-frequency 10 kHz SCS to conventional frequency stimulation performed in 198 subjects with low back pain found that high-frequency stimulation resulted in a statistically significantly greater reduction in mean opioid consumption (112.7 ± 91.0 mg/d at baseline decreased to 87.9 ± 85.2 mg/d) at 12 months compared with conventional frequency stimulation (125.3 ± 150.0 decreased to 118.0 ± 113.2 mg/d).25 However, the percentage of individuals who were able to reduce or stop opioids was not significantly higher (36% vs 26%).25 Further, there was no intragroup difference in the amount of opioid used at the start of stimulation compared to 12-month follow-up25 (Table). A follow-up study published by the same group using 24-month follow-up data did not address changes in opioid use.39
Rationale for Nonopioid-Based Chronic Pain Treatment Options
Interventional pain procedures are viable options to address chronic pain, and may result in decreased opioid use. Because opioid misuse, abuse, and overdose continue to be public health crises, the refinement of interventional therapies has become especially crucial as a nonpharmacological and nonopioid means to control pain. The reported reduction in opioid use afforded by interventional therapy is dependent on the patient, type of pain that is being addressed, and type of procedure. A priority of future pain research must be the effectiveness of interventions to reduce opioid use to treat chronic pain patients, which to date has only been addressed as a secondary outcome measure; in a practical sense, this means that studies have not been adequately powered to address this issue.
The use of opioid therapy may be associated with myriad negative outcomes to include addiction and death, such that the practice of COT for CNCP is now considered controversial.2 Conversely, the consequences of undertreating chronic pain present a need for nonpharmacological and nonopioid pain treatment strategies, such as interventional pain procedures. Identification of interventional pain procedures that are effective at reducing opioid use is an important step in the management of chronic pain.
Limitations in the Reporting of Opioid Use in Studies Evaluating Procedural Interventions
Infrequent reporting of changes in opioid use as a metric for interventional effectiveness may be multifactorial and due to reasons such as researcher bias, lack of awareness, absence of surveillance, or low research interest. An occasional goal for referral of patients to chronic pain clinics is to minimize opioid use. The significant risks associated with COT for CNCP have recently been underscored by several professional organizations, who recommend trials with nonopioid treatments before considering opioid therapy, and stringent prescribing guidelines.2,3 This recent position should be contrasted to that espoused several decades ago, when opioids were considered by many to be a cornerstone of chronic pain therapy, supported by extrapolations of the World Health Organization ladder that was intended for the treatment of cancer pain.40,41 Opioid reduction was not historically considered to be a major therapeutic goal, so few previous clinical trials prioritized it. Currently, the US Food and Drug Administration’s (FDA’s) position is that a meaningful increase in analgesic usage precludes designation as a positive outcome; yet, many earlier studies failed to monitor, let alone control for, the use of cointerventions, including rescue opioids. It is possible that earlier studies reporting positive results with interventional therapies may have been a consequence of altered opioid usage patterns. None of the trials presented in this review evaluated opioid reduction as a primary end point, nor were they powered to demonstrate differences in opioid use after an intervention. Auspiciously, no studies were found that reported higher opioid use after a procedure. However, increases in opioid use after an interventional procedure may have occurred but were not reported. Nonstatistically powered reporting of changes in opioid use, coupled with the subjective nature of pain, make interpretation of the findings in those studies that have reported opioid consumption difficult.
Intervention-derived reductions in pain may not occur contemporaneously with a patient’s ability to reduce opioid use, especially in patients with a prolonged history of opioid therapy or who require relatively high doses. These frequently encountered situations may require a more gradual reduction in opioid dose that is not captured during the data collection period.42 Gradual de-escalation of opioids has been studied and may be applied to clinical situations requiring slow titration after interventional therapy, with various strategies described such as tying opioid reduction to other outcome measures. A study in 50 patients receiving care at a Veterans Administration hospital required 12 months to achieve an average reduction of 46% in opioid consumption and resulted in either decreased or no change in pain severity in 70% of subjects.43 However, over 20% of subjects were excluded from the analysis in this chart review because they exhibited aberrant, drug-seeking behavior, which limits generalization. Even studies that have examined medication usage as a secondary outcome measure often do not provide details on how patients were instructed to reduce analgesic consumption, which can reduce the chances of meeting a predetermined benchmark.23 When successful, long-term tapering of opioid therapy often results in increased functionality without increased pain, with many subjects reporting a reduction in overall pain after opioid tapering.42
Reasons Interventions May Fail to Result in Opioid Reduction
The complex relationship between chronic pain and opioid use may prevent measured reductions in opioid use from being a valid outcome for interventional pain studies. There are many reasons that a pain-alleviating intervention may fail to yield a meaningful reduction in opioid consumption (Figure). Pain is the individual’s interpretation of unpleasant sensations that will produce subjective and difficult-to-reproduce results when used as a primary end point in studies. Chronic pain is modulated by many comorbid social and psychological factors, such as depression, anxiety, personality disorders, poor coping skills, social support systems, sleep patterns, and substance use disorders.42 The development of chronic pain is well established to be associated with a greater prevalence of psychiatric and mood disorders, and these comorbidities may limit the ability to detect decreases in opioid use.44 A study in 81 patients with chronic low back pain treated with COT resulted in poorer treatment outcomes, such as misuse and more severe opioid withdrawal symptoms, in subjects with affective comorbidities at 6 months.45 Similarly, chronic pain may cause an exacerbation of psychiatric, functional and social difficulties such as depression, and low appetite and energy levels, which can influence opioid use.46 For example, opioids were used for many years to treat mood disorders, and it is well established that a strong social support system, full-time employment, and higher income levels may serve protective functions against opioid misuse. Opioid reduction after interventional therapy, or a lack thereof, could therefore be biased as a result of the interaction of chronic pain, psychiatric comorbidities, and opioid use.47–50
Acute tapering of opioids will sometimes result in a transient hyperalgesic state that may predispose rapid or aggressive tapering strategies to the development of acutely worsening pain and premature failure.51,52 Subjects participating in studies may also not have been utilizing opioids at the time of the intervention. To fully understand the prognostic benefit of an intervention, a subgroup analysis would be necessary to detect the observed differences in treatments based on opioid use at the time of procedure. Furthermore, there are patients who have biological or psychosocial predisposing factors that are associated with the use of COT for CNCP.53–55
In addition to their analgesic properties, opioids possess myriad other effects that can pose obstacles to tapering. For example, preclinical and clinical studies have found that the acute withdrawal of opioids may result in anxiety and sleep deprivation, both of which may lower pain thresholds and amplify pain intensity.56,57 Abrupt decreases in opioid usage may result in a heightened adrenergic state manifesting as a disagreeable constellation of irritability, anxiety, myalgias coupled with a several-day increase in overall pain that increases the likelihood of recidivism (ie, retitration to previous levels).46,52 In addition, the transient benefit afforded by some interventions, such as ESI, might not be sufficient to facilitate opioid reduction in a short-term setting. It is not known whether serial ESIs would obviate this shortcoming.
Flaws in Studies Reporting Analgesic Reduction
COT for treatment of acute back pain is warranted, but data supporting use beyond several months are lacking.58 Chronic pain patients are likely to have diverse use patterns for a variety of opioid pain medications, due to preference, efficacy, expectations, and side effects. This variability in opioid-use methodology distorts the interpretation of reported decreases in opioid use. Some studies attempt to standardize opioid reduction by reporting equivalent milligrams of oral morphine. The conversion of 1 opioid to another is a highly imperfect calculation due to the wide interindividual variable responses to opioids.59 In addition, most of the studies in this review examined only total analgesic medication reduction rather than specific opioid-use reduction. Many of the articles cited here employed a standard categorical measure of either a 20% or greater decrease in opioid or cessation of a nonopioid medication as the criterion for “medication reduction” without separating the 2, making the evaluation of an intervention to reduce opioid use difficult.
Perhaps the most methodologically rigorous studies are industry-sponsored trials that seek to provide evidence supporting an FDA indication for a pain condition. Industry-sponsored studies tend to have more stringent inclusion criteria and are more than 3 times as likely to yield positive results than nonindustry-sponsored studies, yielding questions regarding their generalizability.60–62 Moreover, they are more likely to exclude potential participants based on concomitant medication use, and do not generally report results longer than 12 weeks after treatment initiation.61 This latter point is particularly relevant given the high rate of recidivism in patients misusing opioids. Although recent industry-sponsored studies are more likely to report changes in analgesic consumption than studies conducted in previous decades, a recent literature search revealed that most still do not report general analgesic usage, let alone opioid-specific consumption.63,64
Many individuals seeking care with an interventional pain physician do so primarily to treat their pain and not to reduce opioid use. Consequently, most of the literature evaluating procedural interventions has focused on the reduction of pain rather than secondary outcomes, such as reductions in opioid or other analgesic use. Changes in opioid use during observation periods are not always reported, because they are difficult to standardize in study protocols. As an increasing number of patients are referred to pain physicians for opioid-reduction strategies, the goals of clinical care and research should converge to incorporate changes in analgesic medication in addition to changes in pain and functional status.
In conclusion, measurement of opioid reduction after an intervention is a useful metric for guiding clinical practice and should be reported, at least as a secondary outcome, in future studies evaluating interventions. However, there are many obstacles that exist in demonstrating that interventions can reduce opioid consumption, including that studies are generally powered to detect pain relief or functional improvement rather than opioid use; that patients on high-dose opioids are more likely to be excluded from participation; and that acute opioid reduction may result in unintended consequences such as sleep deprivation, anxiety and hyperalgesia, that may reduce the likelihood of a sustained, positive treatment outcome. Although there is increased recognition in the pain medicine community that medication usage should be measured as a secondary outcome, a significant proportion of clinical trials continue to omit this variable. Future studies should endeavor to include a comparison of opioid use before the intervention to after the intervention, with realistic time frames and benchmarks to quantify it.
Name: Dermot P. Maher, MD.
Contribution: This author contributed to the concept design, wrote the manuscript, and created the table and figure.
Conflicts of Interest: None.
Name: Steven P. Cohen, MD.
Contribution: This author contributed to the concept design, wrote the manuscript, and created the table and figure.
Conflicts of Interest: Dr Cohen serves on the advisory boards of Halyard, Boston Scientific, Zynerba, SPR, and Scintilla.
This manuscript was handled by: Honorio T. Benzon, MD.
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