Estimated Rates of Incident and Persistent Chronic Pain Among US Adults, 2019-2020.

Importance: Chronic pain risk and prognosis estimates are needed to inform effective interventions. Objective: To estimate rates of chronic pain and high-impact chronic pain (HICP) incidence and persistence in US adults across demographic groups. Design, Setting, and Participants: This cohort study examined a nationally representative cohort with 1 year of follow-up (mean [SD], 1.3 [0.3] years). Data from the 2019-2020 National Health Interview Survey (NHIS) Longitudinal Cohort were used to assess the incidence rates of chronic pain across demographic groups. The cohort was created using random cluster probability sampling of noninstitutionalized civilian US adults 18 years or older in 2019. Of 21 161 baseline participants in the 2019 NHIS who were randomly chosen for follow-up, 1746 were excluded due to proxy response(s) or lack of contact information, and 334 were deceased or institutionalized. Of the 19 081 remaining, the final analytic sample of 10 415 adults also participated in the 2020 NHIS. Data were analyzed from January 2022 to March 2023. Exposures: Self-reported baseline sex, race, ethnicity, age, and college attainment. Main Outcomes and Measures: Primary outcomes were the incidence rates of chronic pain and HICP, and secondary outcomes were the demographic characteristics and rates across demographic groups. A validated measure of pain status ("In the past 3 months, how often did you have pain? Would you say never, some days, most days, or every day?") yielded 3 discrete categories each year: pain free, nonchronic pain, or chronic pain (pain "most days" or "every day"). Chronic pain present in both survey years was considered persistent; HICP was defined as chronic pain that limited life or work activities on most days or every day. Rates were reported per 1000 person-years (PY) of follow-up, and age standardized based on the 2010 US adult population. Results: Among 10 415 participants included in the analytic sample, 51.7% (95% CI, 50.3%-53.1%) were female, 54.0% (95% CI, 52.4%-55.5%) were aged 18 to 49 years, 72.6% (95% CI, 70.7%-74.6%) were White, 84.5% (95% CI, 81.6%-85.3%) were non-Hispanic or non-Latino, and 70.5% (95% CI, 69.1%-71.9%) were not college graduates. Among pain-free adults in 2019, incidence rates of chronic pain and HICP in 2020 were 52.4 (95% CI, 44.9-59.9) and 12.0 (95% CI, 8.2-15.8) cases per 1000 PY, respectively. The rates of persistent chronic pain and persistent HICP in 2020 were 462.0 (95% CI, 439.7-484.3) and 361.2 (95% CI, 265.6-456.8) cases per 1000 PY, respectively. Conclusions and Relevance: In this cohort study, the incidence of chronic pain was high compared with other chronic diseases. These results emphasize the high disease burden of chronic pain in the US adult population and the need for early management of pain before it becomes chronic.

Comparison Between Preoperative Methadone and Buprenorphine Use on Postoperative Opioid Requirement: A Retrospective Cohort Study.

OBJECTIVES: Buprenorphine is a partial agonist at mu-opioid receptors and competes for these receptors with other opioids in vitro. Whether patients on buprenorphine maintenance require high doses of opioid analgesics to attain adequate postoperative pain control has not been determined. We evaluated differences in acute postoperative opioid consumption and pain burden between patients taking buprenorphine and those taking methadone preoperatively. MATERIALS AND METHODS: A retrospective review of medical records of 928 patients, of whom 195 were on buprenorphine and 733 were on methadone preoperatively, was performed. Among methadone and buprenorphine patients, 615 and 89, respectively, continued to receive the medications postoperatively. Buprenorphine patients were compared with methadone patients for the first 48 hours postoperatively with regard to acute opioid dose requirements (morphine milligram equivalents [MME] above their baseline buprenorphine and methadone doses) and time-weighted average (TWA) pain scores (using targeted maximum likelihood estimation). RESULTS: Opioid dose requirements for 48 hours postoperatively were 150 (22 to 297) (median [interquartile range]) and 220 [90 to 360] MME for buprenorphine and methadone patients, respectively. Preoperative buprenorphine was associated with a 59.9% lower postoperative MME (95% confidence interval: 46.6%-69.8%, P<0.0001) compared with methadone. Postoperative TWA pain scores for the first 48 hours were 5.0±2.7 (mean±SD), and 5.4±2.3 for buprenorphine and methadone patients, respectively. Preoperative buprenorphine was associated with a 0.37-point lower TWA pain score (95% confidence interval: 0.14-0.61, P=0.002) compared with methadone. DISCUSSION: Preoperative buprenorphine use was associated with >50% reduction in postoperative opioid dose requirement and a statistically significant, though clinically unimportant, reduction in acute pain burden in comparison to methadone. The study is limited by several important factors such as the exclusion of patients requiring intravenous patient-controlled analgesia, small number of patients were on higher dose of buprenorphine, and a large percentage of methadone patients were not on a stable dose of methadone yet.

Elevated customary alcohol consumption attenuates opioid effects.

BACKGROUND: Regular alcohol consumption is on the rise among older adults and has the potential of altering the subjective experience of pain and response to pain medications. This study examined the cognitive, analgesic and side effect response to oxycodone in middle age and older adults with elevated levels of customary alcohol consumption in a human laboratory setting. METHODS: After refraining from alcohol for one day, eligible participants underwent baseline assessment cognition and side effects by means of questionnaires that were repeated at three time points (90 min, 5 and 8 h) following administration of a 10 mg oral dose of oxycodone. Response to pain stimulus (Cold Pressor Test (CPT)), pupil size, and plasma oxycodone were also measured. RESULTS: One hundred twenty-eight adults (age 35-85) completed the study day. Compared to those with lower customary alcohol consumption, participants with elevated alcohol consumption showed attenuated opioid-induced pupil constriction and cognitive decline on objective measures of working memory, sustained attention, inhibitory control, coordination on a simulated driving task, and subjective dysphoric effects with enhanced subjective euphoric effects. Oxycodone pharmacokinetics, pain tolerance to CPT, and Berg balance were impacted comparably between alcohol consumption groups. Women endorsed greater negative drug effects, whereas men endorsed positive drug effects. CONCLUSION: Independent of subject's age, elevated customary alcohol consumption attenuates opioid central effects (i.e., pupil miosis, impaired cognition) and gender influences subjective drug effects. Clinicians should consider alcohol consumption and gender when prescribing opioid medications.

AAAPT Diagnostic Criteria for Acute Abdominal and Peritoneal Pain After Surgery.

Abdominal and peritoneal pain after surgery is common and burdensome, yet the lack of standardized diagnostic criteria for this type of acute pain impedes basic, translational, and clinical investigations. The collaborative effort among the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, American Pain Society, and American Academy of Pain Medicine Pain Taxonomy (AAAPT) provides a systematic framework to classify acute painful conditions. Using this framework, a multidisciplinary working group reviewed the literature and developed core diagnostic criteria for acute abdominal and peritoneal pain after surgery. In this report, we apply the proposed AAAPT framework to 4 prototypical surgical procedures resulting in abdominal and peritoneal pain as examples: cesarean delivery, cholecystectomy, colorectal surgical procedures, and pancreas resection. These diagnostic criteria address the 3 most common surgical procedures performed in the United States, capture diverse surgical approaches, and may also be applied to other surgical procedures resulting in abdominal and peritoneal pain. Additional investigation regarding the validity and reliability of this framework will facilitate its adoption in research that advances our comprehension of mechanisms, deliver better treatments, and help prevent the transition of acute to chronic pain after surgery in the abdominal and peritoneal region. PERSPECTIVE: Using AAAPT, we present key diagnostic criteria for acute abdominal and peritoneal pain after surgery. We provide a systematic classification using 5 dimensions for abdominal and peritoneal pain that occurs after surgery, in addition to 4 specific surgical procedures: cesarean delivery, cholecystectomy, colorectal surgical procedures, and pancreas resection.

Multidimensional Diagnostic Criteria for Chronic Pain: Introduction to the ACTTION-American Pain Society Pain Taxonomy (AAPT).

UNLABELLED: A variety of approaches have been used to develop diagnostic criteria for chronic pain. The published evidence of the reliability and validity of existing diagnostic criteria is limited, and these criteria have typically not been used in clinical practice. The availability of a widely accepted, consistently applied, and evidence-based taxonomy of diagnostic criteria would improve the quality of clinical research on chronic pain and would be of great value in clinical practice. To address the need for evidence-based diagnostic criteria for the major chronic pain conditions, the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership with the US Food and Drug Administration and the American Pain Society (APS) have collaborated on the development of the ACTTION-APS Pain Taxonomy (AAPT). AAPT provides a multidimensional framework that is applied systematically in the development of diagnostic criteria. This article (1) describes the background and rationale for AAPT; (2) presents the AAPT taxonomy and the specific conditions for which diagnostic criteria have been developed (to be published separately); (3) briefly reviews the 5 dimensions that constitute the AAPT multidimensional framework and describes the 7 accompanying articles that discuss these dimensions and other important issues involving AAPT; and (4) provides an overview of next steps, specifically, the general processes by which the initial set of diagnostic criteria (for which the evidence base has been drawn from the literature, systematic reviews, and secondary analyses of existing databases) will undergo additional assessments of reliability and validity. PERSPECTIVE: To address the need for evidence-based diagnostic criteria for the major chronic pain conditions, the AAPT provides a multidimensional framework that is applied systematically in the development of diagnostic criteria. The long-term objective of AAPT is to advance the scientific understanding of chronic pain and its treatment.

Ventilation and the Response to Hypercapnia after Morphine in Opioid-naive and Opioid-tolerant Rats.

BACKGROUND: Opioid-related deaths are a leading cause of accidental death, with most occurring in patients receiving chronic pain therapy. Respiratory arrest is the usual cause of death, but mechanisms increasing that risk with increased length of treatment remain unclear. Repeated administration produces tolerance to opioid analgesia, prompting increased dosing, but depression of ventilation may not gain tolerance to the same degree. This study addresses differences in the degree to which chronic morphine (1) produces tolerance to ventilatory depression versus analgesia and (2) alters the magnitude and time course of ventilatory depression. METHODS: Juvenile rats received subcutaneous morphine for 3 days (n = 116) or vehicle control (n = 119) and were then tested on day 4 following one of a range of morphine doses for (a) analgesia by paw withdraw from heat or (b) respiratory parameters by plethysmography-respirometry. RESULTS: Rats receiving chronic morphine showed significant tolerance to morphine sedation and analgesia (five times increased ED50). When sedation was achieved for all animals in a dose group (lowest effective doses: opioid-tolerant, 15 mg/kg; opioid-naive, 3 mg/kg), the opioid-tolerant showed similar magnitudes of depressed ventilation (-41.4 ± 7.0%, mean ± SD) and hypercapnic response (-80.9 ± 15.7%) as found for morphine-naive (-35.5 ± 16.9% and -67.7 ± 15.1%, respectively). Ventilation recovered due to tidal volume without recovery of respiratory rate or hypercapnic sensitivity and more slowly in morphine-tolerant. CONCLUSIONS: In rats, gaining tolerance to morphine analgesia does not reduce ventilatory depression effects when sedated and may inhibit recovery of ventilation.

Postoperative opioid-induced respiratory depression: a closed claims analysis.

BACKGROUND: Postoperative opioid-induced respiratory depression (RD) is a significant cause of death and brain damage in the perioperative period. The authors examined anesthesia closed malpractice claims associated with RD to determine whether patterns of injuries could guide preventative strategies. METHODS: From the Anesthesia Closed Claims Project database of 9,799 claims, three authors reviewed 357 acute pain claims that occurred between 1990 and 2009 for the likelihood of RD using literature-based criteria. Previously cited patient risk factors for RD, clinical management, nursing assessments, and timing of events were abstracted from claim narratives to identify recurrent patterns. RESULTS: RD was judged as possible, probable, or definite in 92 claims (κ = 0.690) of which 77% resulted in severe brain damage or death. The vast majority of RD events (88%) occurred within 24 h of surgery, and 97% were judged as preventable with better monitoring and response. Contributing and potentially actionable factors included multiple prescribers (33%), concurrent administration of nonopioid sedating medications (34%), and inadequate nursing assessments or response (31%). The time between the last nursing check and the discovery of a patient with RD was within 2 h in 42% and within 15 min in 16% of claims. Somnolence was noted in 62% of patients before the event. CONCLUSIONS: This claims review supports a growing consensus that opioid-related adverse events are multifactorial and potentially preventable with improvements in assessment of sedation level, monitoring of oxygenation and ventilation, and early response and intervention, particularly within the first 24 h postoperatively.

Intense focused ultrasound stimulation can safely stimulate inflamed subcutaneous tissue and assess allodynia.

BACKGROUND: Potential peripheral sources of deep pain can require invasive evocative tests for their assessment. Here we perform research whose ultimate goal is development of a non-invasive evocative test for deep painful tissue. METHODS: We used a rat model of inflammation to show that intense focused ultrasound (iFU) differentially stimulates inflamed versus control tissue and can identify allodynia. To do so we applied iFU to inflamed and normal tissue below the skin of rats' hind paws and measured the amount of ultrasound necessary to induce paw withdrawal. RESULTS: iFU of sufficient strength (spatial and temporal average intensities ranged from 100-350 W/cm(2)) caused the rat to withdraw its inflamed paw, while the same iFU applied to the contralateral paw failed to induce withdrawal, with sensitivity and specificity generally greater than 90%. iFU stimulation of normal tissue required twice the amount of ultrasound to generate a withdrawal than did inflamed tissue, thereby assessing allodynia. Finally, we verified in a preliminary way the safety of iFU stimulation with acute histological studies coupled with mathematical simulations. CONCLUSIONS: Given that there exist systems to guide iFU deep to the skin, image-guided iFU may one day allow assessment of patient's deep, peripheral pain generators.

Neuropathic tissue responds preferentially to stimulation by intense focused ultrasound.

We tested the hypothesis that neuropathic tissue is more sensitive to stimulation by intense focused ultrasound (iFU) than control tissue. We created a diffusely neuropathic paw in rats via partial ligation of the sciatic nerve, whose sensitivity to iFU stimulation we compared with sham-surgery and normal control paws. We then applied increasing amounts of iFU (individual 0.2 s pulses at 1.15 MHz) to the rats' paws, assaying for their reliable withdrawal from that stimulation. Neuropathic rats preferentially withdrew their injured paw from iFU at smaller values of iFU intensity (84.2 W/cm(2) ± 25.5) than did sham surgery (97.7 W/cm(2) ± 11.9) and normal control (> 223 W/cm(2)) animals, with greater sensitivity and specificity (85% for neuropathic rats and 50% each of sham surgery and normal control rats). These results directly support our hypothesis as well as Gavrilov's idea that doctors may some day use iFU stimulation to diagnose patients with neuropathies.

Ultra-low dose ketamine and memantine treatment for pain in an opioid-tolerant oncology patient.

Patients taking high-dose opioids chronically for tumor-related or neuropathic pain may develop pain that is refractory to opioids. One option for control of such pain is the use of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. We describe a case of opioid-refractory pain that responded to a low-dose IV infusion of ketamine in the inpatient setting. The patient was then successfully transitioned to oral memantine for long-term outpatient management, in a novel use of this oral NMDA receptor antagonist. We present recent findings from basic research on pain mechanisms to explain why opioid tolerance, as in this patient, may contribute to the analgesic benefit of NMDA receptor antagonists.

Decreased substance P and NK1 receptor immunoreactivity and function in the spinal cord dorsal horn of morphine-treated neonatal rats.

UNLABELLED: Opiate analgesic tolerance is defined as a need for higher doses of opiates to maintain pain relief after prolonged opiate exposure. Though changes in the opioid receptor undoubtedly occur during conditions of opiate tolerance, there is increasing evidence that opiate analgesic tolerance is also caused by pronociceptive adaptations in the spinal cord. We have previously observed increased glutamate release in the spinal cord dorsal horn of neonatal rats made tolerant to the opiate morphine. In this study, we investigate whether spinal substance P (SP) and its receptor, the neurokinin 1 (NK1) receptor, are also modulated by prolonged morphine exposure. Immunocytochemical studies show decreased SP- and NK1-immunoreactivity in the dorsal horn of morphine-treated rats, whereas SP mRNA in the dorsal root ganglia is not changed. Electrophysiological studies show that SP fails to activate the NK1 receptor in the morphine-treated rat. Taken together, the data indicate that chronic morphine treatment in the neonatal rat is characterized by a loss of SP effects on the NK1 receptor in lamina I of the neonatal spinal cord dorsal horn. The results are discussed in terms of compensatory spinal cord processes that may contribute to opiate analgesic tolerance. PERSPECTIVE: This article describes anatomical and physiological changes that occur in the spinal cord dorsal horn of neonatal rats after chronic morphine treatment. These changes may represent an additional compensatory process of morphine tolerance and may represent an additional therapeutic target for the retention and restoration of pain relief with prolonged morphine treatment.

Primary afferent NMDA receptors increase dorsal horn excitation and mediate opiate tolerance in neonatal rats.

Repeated exposure to opiates produces analgesic tolerance, which limits their clinical usefulness. Whole-cell voltage-clamped lamina I cells in spinal slices from opiate-tolerant neonatal rats show an increase in miniature, spontaneous, and primary afferent-evoked EPSCs when compared with lamina I cells from opiate-naive rat spinal slices. This increased excitation can be blocked by the NMDA receptor (NMDAR) antagonist APV, apparently acting at NMDARs on primary afferents. Consistent with these results, electron microscopy demonstrates an increased incidence of NMDARs in substance P-containing spinal dorsal horn primary afferent terminals in opiate-tolerant rats. Moreover, superfusion of spinal slices from opiate-tolerant rats with NMDA produces a reversible increase in miniature EPSC (mEPSC) frequency in contrast to a decrease in mEPSC frequency produced by NMDA in opiate-naive slices. Finally, NMDAR antagonists inhibit the expression of opiate tolerance both in inhibiting EPSCs in spinal slices and in inhibiting behavioral nociceptive responses to heat. NMDAR antagonists have been reported in many studies to inhibit morphine analgesic tolerance. Our studies suggest that an increase in primary afferent NMDAR expression and activity mediates a hypersensitivity to noxious stimuli and causes the inhibition of opiate efficacy, which defines tolerance.

Differential effect of glutamate transporter inhibition on EPSCs in the morphine naïve and morphine tolerant neonatal spinal cord slice.

Opioid analgesic tolerance is a phenomenon defined as a need for increasingly higher doses of opiates to maintain suitable pain relief following repeated drug exposure. Research suggests that analgesic tolerance may result from heightened NMDA receptor (NMDAR) activity, but little is known regarding the mechanisms by which this elevated NMDAR activity develops. Recent evidence suggests that glutamate transporter down-regulation follows repeated opiate exposure and contributes to heightened pain sensitivity. Though glutamate transporter inhibition has been shown to increase activity of spinal cord neurons, it is unknown whether this increase contributes to the heightened NMDAR activity that underlies opiate tolerance. We directly tested this hypothesis by comparing the effects of glutamate transporter inhibition on excitatory post-synaptic currents (EPSCs) in the spinal cord dorsal horn of opiate naïve and opiate tolerant rats. We show that non-selective glutamate transporter inhibition increases the rate of spontaneous excitatory post-synaptic currents (sEPSCs) in the opiate naïve, but not opiate tolerant slice. This potentiation occurs in the presence of the sodium channel blocker tetrodotoxin (TTX) and is blocked by the NMDAR antagonist D-2-amino-5-phosphonovalerate (APV). The sEPSC rate is elevated at baseline in the opiate tolerant spinal cord slice compared to the opiate naïve slice, and glutamate transporter inhibition eliminates this difference. Taken together, we conclude that glutamate transporter inhibition directly contributes to heightened NMDAR activity. Furthermore, we propose that the increased neural activity observed in the opiate tolerant slice is due to a state of glutamate transporter down-regulation and resultant heightened NMDAR activity.

APS position statement on the use of placebos in pain management.

In the spring of 2003, the board of directors of the American Pain Society asked the APS Ethics Committee to formulate a position statement for the Society concerning the use of placebos in clinical practice (cf, reference ). A subset of the Ethics Committee under my direction composed such a statement based on the available scientific and ethical literature. We then sought feedback from the entire ethics committee as well as numerous prominent voices in the literature and presented the statement to the membership for discussion at the 2004 annual APS meeting in Vancouver, British Columbia, at both a symposium and an ethics special interest group meeting. The resultant document was approved by the APS Board and is published here for widespread distribution to the membership.

Neuropathic pain activates the endogenous kappa opioid system in mouse spinal cord and induces opioid receptor tolerance.

Release of endogenous dynorphin opioids within the spinal cord after partial sciatic nerve ligation (pSNL) is known to contribute to the neuropathic pain processes. Using a phosphoselective antibody [kappa opioid receptor (KOR-P)] able to detect the serine 369 phosphorylated form of the KOR, we determined possible sites of dynorphin action within the spinal cord after pSNL. KOR-P immunoreactivity (IR) was markedly increased in the L4-L5 spinal dorsal horn of wild-type C57BL/6 mice (7-21 d) after lesion, but not in mice pretreated with the KOR antagonist nor-binaltorphimine (norBNI). In addition, knock-out mice lacking prodynorphin, KOR, or G-protein receptor kinase 3 (GRK3) did not show significant increases in KOR-P IR after pSNL. KOR-P IR was colocalized in both GABAergic neurons and GFAP-positive astrocytes in both ipsilateral and contralateral spinal dorsal horn. Consistent with sustained opioid release, KOR knock-out mice developed significantly increased tactile allodynia and thermal hyperalgesia in both the early (first week) and late (third week) interval after lesion. Similarly, mice pretreated with norBNI showed enhanced hyperalgesia and allodynia during the 3 weeks after pSNL. Because sustained activation of opioid receptors might induce tolerance, we measured the antinociceptive effect of the kappa agonist U50,488 using radiant heat applied to the ipsilateral hindpaw, and we found that agonist potency was significantly decreased 7 d after pSNL. In contrast, neither prodynorphin nor GRK3 knock-out mice showed U50,488 tolerance after pSNL. These findings suggest that pSNL induced a sustained release of endogenous prodynorphin-derived opioid peptides that activated an anti-nociceptive KOR system in mouse spinal cord. Thus, endogenous dynorphin had both pronociceptive and antinociceptive actions after nerve injury and induced GRK3-mediated opioid tolerance.

G-protein receptor kinase 3 (GRK3) influences opioid analgesic tolerance but not opioid withdrawal.

1. Tolerance to opioids frequently follows repeated drug administration and affects the clinical utility of these analgesics. Studies in simple cellular systems have demonstrated that prolonged activation of opioid receptors produces homologous receptor desensitization by G-protein receptor kinase mediated receptor phosphorylation and subsequent beta-arrestin binding. To define the role of this regulatory mechanism in the control of the electrophysiological and behavioral responses to opioids, we used mice having a targeted disruption of the G-protein receptor kinase 3 (GRK3) gene. 2. Mice lacking GRK3 did not differ from wild-type littermates neither in their response latencies to noxious stimuli on the hot-plate test nor in their acute antinociceptive responses to fentanyl or morphine. 3. Tolerance to the electrophysiological response to the opioid fentanyl, measured in vitro in the hippocampus, was blocked by GRK3 deletion. In addition, tolerance to the antinociceptive effects of fentanyl was significantly reduced in GRK3 knockouts compared to wild-type littermate controls. 4. Tolerance to the antinociceptive effects of morphine was not affected by GRK3 deletion although morphine tolerance in hippocampal slices from GRK3 knockout mice was significantly inhibited. Tolerance developed more slowly in vitro to morphine than fentanyl supporting previous work in in vitro systems showing a correlation between agonist efficacy and GRK3-mediated desensitization. 5. The results of these studies suggest that GRK3-mediated mechanisms are important components of both electrophysiologic and behavioral opioid tolerance. Fentanyl, a high efficacy opioid, more effectively produced GRK3-dependent effects than morphine, a low efficacy agonist.

Stress-induced analgesia in the mouse: strain comparisons.

Inescapable footshock is capable of differentially activating opioid- and non-opioid-mediated mechanisms of stress-induced analgesia in the rat, depending on the temporal and intensive parameters of its administration. In this study we compared the effects of opioid and non-opioid stress analgesia in two strains of mice, one known to be deficient in central opioid binding sites (CXBK) and one normal in this regard (C57BL/6BY). We found that although the C57 strain showed robust opioid and non-opioid stress analgesia, the CXBK strain only showed stress analgesia of the non-opioid type.