Non-pharmacological interventions for managing pain in community-dwelling older adults

Pain is a complex and common issue within older adults. This complexity can be a direct result of comorbidities and the subsequent polypharmacy. The effective control of pain in older adults needs more than just pharmacological management. Non-pharmacological interventions have been demonstrated to be beneficial when combined with pain medications. This commentary critically appraises a systematic review that examines the effectiveness of non-pharmacological interventions for the management of pain in community dwelling older adults.

Prescription Patterns and Relationship to Pharmacogenomics Testing in the Military Health System

ABSTRACT Introduction Clinical utilization of pharmacogenomics (PGx) testing is highly institutionally dependent, and little information is known about provider practices of PGx testing in the Military Health System (MHS). In this study, we aimed to characterize Clinical Pharmacogenetics Implementation Consortium (CPIC) actionable prescription (Rx) patterns and their temporal relationship with PGx testing in the MHS. Methods Using data from the Military Health System Management Analysis and Reporting Tool (M2) database, this retrospective cohort study included all patients receiving at least one PGx test and at least one CPIC actionable Rx from January 2015 to August 2020 (845 patients, 1,471 PGx, 7,725 index CPIC actionable Rxs). Rx patterns and temporal relationships with PGx testing were characterized via descriptive statistics. Binomial regression was used to determine which patient and provider characteristics were associated with a patient receiving a PGx test within 30 days of an index Rx. Results Patients had a median of 9 index CPIC actionable Rx’s (range 1–26). Pain medications were most commonly prescribed (N = 794, 94% patients with at least 1 Rx). However, pain medication had the lowest Rx–PGx match rate (40%) compared to an average of 62% Rx–PGx match rate for all CPIC drugs. Antidepressants were also commonly prescribed (N = 668, 79.1% patients with at least 1 Rx), and antidepressants had the highest Rx–PGx match rate of 86.7%. A minority of providers (20%, N = 249) ordered the majority of PGx tests (86.1%, N = 1,266) and only 8.3% of PGx tests (N = 398) matched to a CPIC actionable drug within 30 days of the test (defined by Rxs ordered within 30 days before or after the PGx test). However, approximately 39.8% of patients (N = 317) had at least one drug match to a PGx test within 30 days. The largest predictor of whether a patient received a PGx test within 30 days of any index Rx was whether or not a specific psychiatry provider ordered the PGx test (odds ratio; OR 3.7, 95% CI 2.13–6.54, P < 0.001). Neither the CPIC level of evidence nor FDA PGx actionable or informative labels had a significant effect on PGx test timing. Conclusions PGx testing was generally limited to high Rx-drug users and was found to be an under-utilized resource. PGx testing did not typically follow CPIC guidelines. Implementing PGx testing protocols, simplifying PGx test-ordering by incorporating at minimum CYP2D6, CYP2C19, and CYP2C9 into PGx-testing panels, and unifying providers’ PGx knowledgebase in the MHS are feasible and would improve the clinical utilization of PGx tests in the MHS.

The Safety of Benzodiazepines and Opioids in the Geriatric Population: An Analysis of Patient Safety Events Reported by Hospitals and Ambulatory Surgical Facilities

Benzodiazepines may increase the risk of cognitive impairment, delirium, falls, fractures, and motor vehicle crashes in patients 65 years and older. The concomitant use of benzodiazepines and opioids may also be inappropriate for older adults due to the increased risk of overdose. We searched the Pennsylvania Patient Safety Reporting System (PA-PSRS) for reports of patient safety events related to the concomitant use of benzodiazepines and opioids in older adults in order to gain a better understanding of the potential risks of using these medications in combination. We identified 80 reports in which a patient may have experienced an adverse drug reaction (ADR) to the combined use of a benzodiazepine and an opioid pain medication. Reports were reviewed to determine the ADR(s) experienced by the patient. Changes in mental status were most common, occurring in more than two-thirds of reports (68.8%; 55 of 80), followed by respiratory reactions (51.3%; 41 of 80) and cardiovascular reactions (25.0%; 20 of 80). In over two-thirds of reports (70.0%; 56 of 80), the patient received a reversal agent, either flumazenil (10.7%; 6 of 56) or naloxone (35.7%; 20 of 56), or both (53.6%; 30 of 56). The inappropriate use of benzodiazepines and opioid pain medications in combination among patients 65 years and older is a growing problem, and an increased awareness may be the first step for providers to begin addressing it.

Investigating the anti-cocaine, anti-nociceptive properties and side effects of MP1104, a novel mixed opioid receptor agonist

<p>Rationale: Drug addiction is a chronic, relapsing disease with great socioeconomic and morbidity costs. There are limited treatments, with no Food and Drug Administration approved pharmacotherapies available for psychostimulant addiction. In addition, the use of prescription opioid medications has reached epidemic proportions in the world. More than 40,000 deaths from prescription opioid overdose was reported in USA alone in the year 2017. There is an urgent need for the development of effective, non-addictive pain medications and addiction treatments. The opioid receptors play an important role in the modulation of pain and addiction. Mu opioid receptor (MOPr) agonists are widely used to treat pain, however, can also induce respiratory depression, tolerance and addiction. In contrast, drugs activating the kappa opioid receptor (KOPr) attenuate the rewarding properties of drugs, hence are promising non-addictive analgesics. However, side effects like aversion, sedation, anxiety and depression limit their clinical utility. Delta opioid receptor (DOPr) agonists have rewarding, anti-nociceptive and anti-depressive properties, but can also cause seizures. We hypothesise that development of mixed opioid receptor ligands may have therapeutic properties with reduced side effects. Therefore, this thesis evaluated MP1104, a potent mixed opioid receptor agonist, with full efficacy at all three receptors and 3- and 13-fold higher binding affinity for KOPr compared to MOPr and DOPr, respectively. MP1104 was evaluated for the ability to modulate cocaine-induced behaviours, the anti-nociceptive effects and side effects. Methods: Male Sprague-Dawley rats were used to investigate the effects of acute MP1104 treatment on cocaine self-administration and drug seeking behaviour. To determine the mechanism, the modulatory effect of MP1104 on dopamine transporter (DAT) function was assessed using rotating disk electrode voltammetry to measure dopamine uptake in rat dorsal striatum (dStr) and nucleus accumbens (NAc) tissue. Evaluation of side effects included sedation (spontaneous locomotor activity), anxiety (elevated plus maze (EPM)), aversion (conditioned place aversion (CPA)) and depression (forced swim tests (FST)) in rats. The anti-nociceptive effects were measured in the warm-water tail withdrawal assay in rats and male C57BL/6 mice. Acute and chronic administration of MP1104 were evaluated in the paclitaxel-induced neuropathic pain model in mice. Results: In rats trained to self-administer cocaine, acute MP1104 (0.3 and 1 mg/kg, i.p.) administration reduced cocaine-primed reinstatement of drug seeking behaviour and caused a significant downward shift in the cocaine dose-response curve. The anti-cocaine effects exerted by MP1104 are in part due to increased dopamine uptake by DAT in the NAc, which was KOPr-mediated. In the warm-water tail withdrawal assay in rats, acute administration of MP1104 (0.3 and 0.6 mg/kg, i.p.) was 4 times longer acting (8 h) than morphine (2 h). These effects were both KOPr and DOPr dependent. In the dose-response tail withdrawal assay, MP1104 was found to be potent in both rats (ED₅₀ = 0.58 mg/kg, s.c.) and mice (ED₅₀ = 0.35 mg/kg, s.c.). In the paclitaxel-induced neuropathic pain model, mice treated with MP1104 showed potent reductions in both mechanical (ED₅₀ = 0.449 mg/kg, s.c.) and cold (ED₅₀ = 0.479 mg/kg, s.c.) allodynia compared to morphine. Following chronic daily administration of the ED₈₀ dose, MP1104 (1.2 mg/kg, i.p.) was more potent than morphine in reducing mechanical and cold allodynia. Surprisingly, MP1104 reversed responding back to baseline (non-disease) levels. The most remarkable finding was that MP1104, unlike morphine did not produce tolerance when administered chronically. When the side effects of MP1104 were evaluated in rats, no significant anxiogenic effects were seen in the EPM, nor pro-depressive effects in the FST, nor aversion in CPA tests in rats. Furthermore, pre-treatment with a DOPr antagonist, led to MP1104 producing aversive effects. This data suggests that the DOPr agonist actions of MP1104 attenuate the KOPr-mediated aversive effects of MP1104. However, at higher doses, MP1104 (1 mg/kg, i.p.) was found to be sedative. Conclusions: MP1104 exerts potent anti-cocaine properties in self-administration tests. The reduced cocaine reward is at least in part due to the ability of MP1104 to modulate DAT function by increasing dopamine uptake in the NAc. MP1104 is also a potent and long-lasting anti-nociceptive agent in rats. Significantly, when evaluated in a chronic neuropathic pain model, MP1104 was potent with no tolerance to the anti-nociceptive effects observed. Moreover, MP1104 showed fewer side effects with reduced sedative effects and no observed anxiety, aversive, nor pro-depressive effects, unlike pure KOPr agonists. This data supports the therapeutic development of mixed opioid receptor agonists, particularly mixed KOPr/DOPr agonists as non-addictive pain medications and anti-cocaine pharmacotherapies with fewer side effects.</p>

Investigating the anti-cocaine, anti-nociceptive properties and side effects of MP1104, a novel mixed opioid receptor agonist

<p>Rationale: Drug addiction is a chronic, relapsing disease with great socioeconomic and morbidity costs. There are limited treatments, with no Food and Drug Administration approved pharmacotherapies available for psychostimulant addiction. In addition, the use of prescription opioid medications has reached epidemic proportions in the world. More than 40,000 deaths from prescription opioid overdose was reported in USA alone in the year 2017. There is an urgent need for the development of effective, non-addictive pain medications and addiction treatments. The opioid receptors play an important role in the modulation of pain and addiction. Mu opioid receptor (MOPr) agonists are widely used to treat pain, however, can also induce respiratory depression, tolerance and addiction. In contrast, drugs activating the kappa opioid receptor (KOPr) attenuate the rewarding properties of drugs, hence are promising non-addictive analgesics. However, side effects like aversion, sedation, anxiety and depression limit their clinical utility. Delta opioid receptor (DOPr) agonists have rewarding, anti-nociceptive and anti-depressive properties, but can also cause seizures. We hypothesise that development of mixed opioid receptor ligands may have therapeutic properties with reduced side effects. Therefore, this thesis evaluated MP1104, a potent mixed opioid receptor agonist, with full efficacy at all three receptors and 3- and 13-fold higher binding affinity for KOPr compared to MOPr and DOPr, respectively. MP1104 was evaluated for the ability to modulate cocaine-induced behaviours, the anti-nociceptive effects and side effects. Methods: Male Sprague-Dawley rats were used to investigate the effects of acute MP1104 treatment on cocaine self-administration and drug seeking behaviour. To determine the mechanism, the modulatory effect of MP1104 on dopamine transporter (DAT) function was assessed using rotating disk electrode voltammetry to measure dopamine uptake in rat dorsal striatum (dStr) and nucleus accumbens (NAc) tissue. Evaluation of side effects included sedation (spontaneous locomotor activity), anxiety (elevated plus maze (EPM)), aversion (conditioned place aversion (CPA)) and depression (forced swim tests (FST)) in rats. The anti-nociceptive effects were measured in the warm-water tail withdrawal assay in rats and male C57BL/6 mice. Acute and chronic administration of MP1104 were evaluated in the paclitaxel-induced neuropathic pain model in mice. Results: In rats trained to self-administer cocaine, acute MP1104 (0.3 and 1 mg/kg, i.p.) administration reduced cocaine-primed reinstatement of drug seeking behaviour and caused a significant downward shift in the cocaine dose-response curve. The anti-cocaine effects exerted by MP1104 are in part due to increased dopamine uptake by DAT in the NAc, which was KOPr-mediated. In the warm-water tail withdrawal assay in rats, acute administration of MP1104 (0.3 and 0.6 mg/kg, i.p.) was 4 times longer acting (8 h) than morphine (2 h). These effects were both KOPr and DOPr dependent. In the dose-response tail withdrawal assay, MP1104 was found to be potent in both rats (ED₅₀ = 0.58 mg/kg, s.c.) and mice (ED₅₀ = 0.35 mg/kg, s.c.). In the paclitaxel-induced neuropathic pain model, mice treated with MP1104 showed potent reductions in both mechanical (ED₅₀ = 0.449 mg/kg, s.c.) and cold (ED₅₀ = 0.479 mg/kg, s.c.) allodynia compared to morphine. Following chronic daily administration of the ED₈₀ dose, MP1104 (1.2 mg/kg, i.p.) was more potent than morphine in reducing mechanical and cold allodynia. Surprisingly, MP1104 reversed responding back to baseline (non-disease) levels. The most remarkable finding was that MP1104, unlike morphine did not produce tolerance when administered chronically. When the side effects of MP1104 were evaluated in rats, no significant anxiogenic effects were seen in the EPM, nor pro-depressive effects in the FST, nor aversion in CPA tests in rats. Furthermore, pre-treatment with a DOPr antagonist, led to MP1104 producing aversive effects. This data suggests that the DOPr agonist actions of MP1104 attenuate the KOPr-mediated aversive effects of MP1104. However, at higher doses, MP1104 (1 mg/kg, i.p.) was found to be sedative. Conclusions: MP1104 exerts potent anti-cocaine properties in self-administration tests. The reduced cocaine reward is at least in part due to the ability of MP1104 to modulate DAT function by increasing dopamine uptake in the NAc. MP1104 is also a potent and long-lasting anti-nociceptive agent in rats. Significantly, when evaluated in a chronic neuropathic pain model, MP1104 was potent with no tolerance to the anti-nociceptive effects observed. Moreover, MP1104 showed fewer side effects with reduced sedative effects and no observed anxiety, aversive, nor pro-depressive effects, unlike pure KOPr agonists. This data supports the therapeutic development of mixed opioid receptor agonists, particularly mixed KOPr/DOPr agonists as non-addictive pain medications and anti-cocaine pharmacotherapies with fewer side effects.</p>

An Analysis of Ketamine Doses Administrated to Nonintubated Casualties Prehospital

ABSTRACT Introduction Previous studies demonstrate that a significant proportion of casualties do not receive pain medication prehospital after traumatic injuries. To address possible reasons, the U.S. Military has sought to develop novel delivery methods to aid in administration of pain medications prehospital. We sought to describe the dose and route of ketamine administered prehospital to help inform materiel solutions. Materials and Methods This is a secondary analysis of a previously described dataset focused on prehospital data within the Department of Defense Trauma Registry from 2007 to 2020. We isolated encounters in which ketamine was administered along with the amount dosed and the route of administration in nonintubated patients. Results Within our dataset, 862 casualties met inclusion for this analysis. The median age was 28 and nearly all (98%) were male. Most were battle injuries (88%) caused by explosives (54%). The median injury severity score was 10 with the extremities accounting to the most frequent seriously injured body region (38%). The mean dose via intravenous route was 50.4 mg (n = 743, 95% CI 46.5-54.3), intramuscular was 66.7 mg (n = 234, 95% CI 60.3-73.1), intranasal was 56.5 mg (n = 10, 39.1-73.8), and intraosseous was 83.3 mg (n = 34, 66.3-100.4). Most had a medic or CLS in their chain of care (87%) with air evacuation as the primary mechanism of evacuation (86%). Conclusions The average doses administered were generally larger than the doses recommended by Tactical Combat Casualty Care guidelines. Currently, guidelines may underdose analgesia. Our data will help inform materiel solutions based on end-user requirements.

Analgesic use in adolescents with patellofemoral pain or Osgood–Schlatter Disease: a secondary cross-sectional analysis of 323 subjects

Objectives The prevalence of pain medication use for adolescent knee pain and factors associated with use are not well understood. This study aimed to determine the self-reported use of pain medication for knee pain and identify factors associated with use in adolescents (age 10–19) with longstanding knee symptoms. Methods In this exploratory cross-sectional study, we performed a secondary analysis of data previously collected in 323 adolescents with longstanding knee pain. Factors associated with pain medication use were assessed using multivariable logistic regressions. Analyses were repeated with stratification by age, sex, sport participation frequency, knee pain duration, and knee pain intensity. Results Among 323 adolescents (mean age 14.4 ± 2.5, 73% female), 84% had patellofemoral pain, (peri- or retro-patellar pain during loaded bending of the knee) and 16% had Osgood–Schlatter Disease (apophysitis with swelling and localized pain at the tibial tuberosity). Twenty-one percent (95% CI 16–25%) of adolescents reported pain medication use for their knee pain, with no difference in usage between those ≤ vs. > 15 years of age (21%, 95% CI 16–27% vs. 20%, 95% CI 13–29%). Adolescents with patellofemoral pain reported greater usage than their counterparts with Osgood–Schlatter Disease (22%, 95% CI 17–28% vs. 12%, 95% CI 4.5–24.3%). The most consistent factor associated with use was knee-related symptoms, observed in both the overall (OR 0.97, 95% CI 0.94–0.99) and stratified analyses (ORs ranged from 0.89 to 0.96). Conclusions Approximately one in five adolescents with longstanding knee pain reported pain medication use, particularly in adolescents with patellofemoral pain. Knee-related symptoms most consistently associated with the use of pain medications in this population. Future longitudinal studies with data collected at multiple time-points are needed to validate these findings. Implications Self-reported pain medication use is common in adolescents with longstanding knee pain, even though whether pharmacological therapy is the best pain management option at this young age is debatable. Reliance on pain medication at an early age could potentially hamper the development of healthy pain coping strategies and increase the risk of dependence and misuse later in life. Future studies should assess the safety, efficacy, and risks of long-term use of pain medications for adolescent knee pain.

Exploring Knowledge, Beliefs, and Attitudes of Older Adults About Prescription Opioids

Over the past two decades, opioids have been considered important and acceptable in the treatment of pain for older adults, especially for chronic health conditions. Despite the fact that older adults are prescribed opioid medications at high rates, there is little research examining older adults’ knowledge, beliefs, and attitudes about opioid medications. The purpose of this study was to explore the knowledge, beliefs, and attitudes surrounding prescription opioid medications of community living older adults in a southeast area of the United States. A cross-sectional, descriptive, anonymous survey design of participants aged 55 or over was used. Study participants (N=119) reported bias in their attitudes and beliefs about the use and misuse of prescription opioid medications. Multiple regression analyses revealed that gender, age, work, marital status, and education level all had significant results in explaining variance in the statistical models. Even though study participants demonstrated high levels of education and understanding of the potential of addiction to opiates, there were a number of misconceptions revealed about prescription pain medications. This urges the necessity of increased awareness via further research, presentations, and creative discourse to assist in the understanding of precursors of addiction and ways to deal with pain that do not automatically rely on prescription opioid medicines. Implications include outreach to a larger and more diverse sample to address knowledge, beliefs, and attitudes surrounding prescription opioid medications of community living older adults.

A Case Report of Subacute Thyroiditis following mRNA COVID-19 Vaccine

Background. Subacute thyroiditis has been reported after administration of influenza vaccine. We describe a case of a patient who developed subacute thyroiditis after administration of. Moderna mRNA COVID-19 vaccine. Case Presentation. A 42-year-old female, with a past medical history of stage IIIB pT3N1aM0 right adenocarcinoma of colon status, after right hemicolectomy on 01/2020, followed by adjuvant chemotherapy, paroxysmal supraventricular tachycardia, iron deficiency anemia, chemotherapy-induced neuropathy, and lumbar radiculopathy, presented to our clinic with anterior neck pain that started 6 days after the second dose of Moderna mRNA COVID-19 vaccine. She was diagnosed with subacute thyroiditis and treated conservatively with pain medications. Conclusion. Subacute thyroiditis could represent one of the side effects of Moderna mRNA COVID-19 vaccine. Further reports are lacking.