Pain management for post-treatment survivors of complex cancers: a qualitative study of opioids and cannabis.

Aim: We aimed to understand experiences with opioids and cannabis for post-treatment cancer survivors. Patients & methods: We conducted seven focus groups among head and neck and lung cancer survivors, using standard qualitative methodology to explore themes around 1) post-treatment pain and 2) utilization, perceived benefits and perceived harms of cannabis and opioids. Results & conclusion: Survivors (N = 25) experienced addiction fears, stigma and access challenges for both products. Opioids were often perceived as critical for severe pain. Cannabis reduced pain and anxiety for many survivors, suggesting that anxiety screening, as recommended in guidelines, would improve traditional pain assessment. Opioids and cannabis present complex harms and benefits for post-treatment survivors who must balance pain management and minimizing side effects.

An Assessment of the One-Month Effectiveness of Telehealth Treatment for Opioid Use Disorder Using the Brief Addiction Monitor.

OBJECTIVES: Telehealth treatment with medication for opioid use disorder (teleMOUD) was made possible with regulations following the COVID-19 pandemic that permitted prescribing buprenorphine without an in-person visit. This study evaluates the self-reported outcomes of patients treated by teleMOUD using the Brief Addiction Monitor (BAM), a 17-question tool that assesses drug use, cravings, physical and psychological health, and psychosocial factors to produce 3 subset scores: substance use, risk factors, and protective factors. METHODS: Patients treated by a teleMOUD provider group operating in >30 states were asked to complete an app-based version of BAM at enrollment and at 1 month. Patients who completed both assessments between June 2022 and March 2023 were included. RESULTS: A total of 2556 patients completed an enrollment BAM and 1447 completed both assessments. Mean number of days from baseline BAM to follow-up was 26.7 days. Changes were significantly different across most questions. The substance use subscale decreased from mean 2.6 to 0.8 (P < .001), the risk factors subscale decreased from mean 10.3 to 7.5 (P < .001), and the protective factors subscale increased from mean 14.3 to 15.0. (P < .001). Substance use and risk factor subscale changes were significant across all sex and age groups, while protective factors subscale did not improve for those <25 and >54 years. Patient reports of at least 1 day of illegal use or misuse decreased, including marijuana (28.1% vs 9.0%), cocaine/crack (3.9% vs 2.6%), and opioids (49.8% vs 10.5%). CONCLUSIONS: Among patients treated by teleMOUD who completed assessments at enrollment and 1 month, there was improvement in drug use, risk factor, and protective factor scores.

Neonatal Opioid Withdrawal Syndrome Following Prenatal Use of Supplements Containing Tianeptine.

Tianeptine is an opioid receptor agonist that is prescribed as an antidepressant in many countries. In the United States, tianeptine is not approved for medical use because of its potential for abuse and addiction. Nonetheless, products containing tianeptine are easily obtainable and are marketed as dietary supplements. There are increasing reports of adverse effects and fatal toxicities resulting from tianeptine use among adolescents and adults. This emerging public health threat could escalate the opioid epidemic and drive increased newborn perinatal exposure. The impact of in utero exposure to tianeptine has not been studied, and to our knowledge, the authors of only 1 report have documented possible neonatal effects. Here, we describe a case of chronic prenatal exposure to tianeptine in the setting of maternal dependence on dietary supplements. This infant developed signs of severe withdrawal shortly after birth that were refractory to treatment with oral phenobarbital but responded to subsequent oral morphine therapy. On further questioning, the mother revealed the use of a tianeptine-containing dietary supplement. We did not perform confirmatory toxicology testing because tianeptine is not assayed by usual urine drug screening tests. For infants with clinical signs of opioid withdrawal without known etiology, we suggest that the maternal interview should inquire about the use of neurotropic over-the-counter drugs.

Antinociceptive Effect of Dillenia indica (Linn.) Mediated by Opioid and Cannabinoid Systems: Pharmacological and Chemical Studies.

Dillenia indica (Linn.) has been reported by several biological activities, including anti-inflammatory, antioxidant, antidiabetic, anti-hyperglycemic, antiproliferative, antimutagenic, anticholinesterase, and antimicrobial. In Brazilian traditional medicine, the fruits of D. indica have been used to treat general topical pain and inflammation, but with no scientific validation. Thus, aiming to study its chemical constitution and antinociceptive properties, the crude extract (CE) and fractions obtained from the fruits of D. indica were submitted to an in vivo pharmacological evaluation and a dereplication study by LC-MS/MS analysis, assisted by the Global Natural Product Social Molecular Networking (GNPS). The oral antinociceptive activity of the fruits of D. indica and the possible participation of the opioid and cannabinoid systems were demonstrated in the formalin-induced nociception model. The chemical dereplication study led us to identify several known chemical constituents, including flavonoids, such as caffeoylmalic acid, naringenin, quercetin, and kaempferol. According to literature data, our results are compatible with significant antinociceptive and anti-inflammatory activities. Therefore, the flavonoid constituents of the fruits of D. indica are probably responsible for its antioxidant, anti-inflammatory, and antinociceptive effects mediated by both opioid and cannabinoid systems, confirming its folk use in the treatment and relief of pain.

Nonsteroidal anti-inflammatory drug "allergy" labeling is associated with increased postpartum opioid utilization.

BACKGROUND: Current guidelines recommend a stepwise approach to postpartum pain management, beginning with acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), with opioids added only if needed. Report of a prior NSAID-induced adverse drug reaction (ADR) may preclude use of first-line analgesics, despite evidence that many patients with this allergy label may safely tolerate NSAIDs. OBJECTIVE: We assessed the association between reported NSAID ADRs and postpartum opioid utilization. METHODS: We performed a retrospective cohort study of birthing people who delivered within an integrated health system (January 1, 2017, to December 31, 2020). Study outcomes were postpartum inpatient opioid administrations and opioid prescriptions at discharge. Statistical analysis was performed on a propensity score-matched sample, which was generated with the goal of matching to the covariate distributions from individuals with NSAID ADRs. RESULTS: Of 38,927 eligible participants, there were 883 (2.3%) with an NSAID ADR. Among individuals with reported NSAID ADRs, 49.5% received inpatient opioids in the postpartum period, compared to 34.5% of those with no NSAID ADRs (difference = 15.0%, 95% confidence interval 11.4-18.6%). For patients who received postpartum inpatient opioids, those with NSAID ADRs received a higher total cumulative dose between delivery and hospital discharge (median 30.0 vs 22.5 morphine milligram equivalents [MME] for vaginal deliveries; median 104.4 vs 75.0 MME for cesarean deliveries). The overall proportion of patients receiving an opioid prescription at the time of hospital discharge was higher for patients with NSAID ADRs compared to patients with no NSAID ADRs (39.3% vs 27.2%; difference = 12.1%, 95% confidence interval 8.6-15.6%). CONCLUSION: Patients with reported NSAID ADRs had higher postpartum inpatient opioid utilization and more frequently received opioid prescriptions at hospital discharge compared to those without NSAID ADRs, regardless of mode of delivery.

Transcutaneous electrical acupoint stimulation for cancer-related pain management in patients receiving chronic opioid therapy: a randomized clinical trial.

PURPOSE: The opioid crisis resulting from its use disorder and overdose poses additional challenges for cancer pain management. The American Society of Clinical Oncology Practice Guideline recommends acupuncture therapy for the management of adult cancer-related pain (CRP), but the effectiveness of transcutaneous electrical acupoint stimulation (TEAS) on CRP remains uncertain. METHODS: This 5-week prospective randomized clinical trial was conducted at 2 hospitals in China, and participants with CRP receiving chronic opioid therapy were randomized 1:1 into two groups between December 2014 and June 2018. The true TEAS group underwent 15 sessions of TEAS treatments over 3 consecutive weeks, while the control group received sham stimulation. The primary outcome was the numerical rating scale (NRS) score in the past 24h at week 3. The secondary outcomes included morphine equivalent daily dose, quality of life and adverse events. RESULTS: A total of 159 participants were included in the modified intention-to-treat population. The baseline characteristics were similar in both groups. The mean NRS scores were 0.98 points at week 3 in the true TEAS group and 1.41 points in the sham group, with the mean difference between groups of -0.43 points (P < 0.001; OR = 0.68, P < 0.05). The proportion of patients with NRS reduction more than thirty percentage at week 3 was 50.00% in the true TEAS group and 35.44% in the sham group (RD = 0.15, P > 0.05; RR = 1.41, P > 0.05). No significant difference in pain intensity between the two groups was observed during the follow-up period without TEAS intervention (week 4, OR = 0.83, P > 0.05; week 5, OR = 0.83, P > 0.05). The Karnofsky Performance Status value suggested that patients in the true TEAS group experienced an improved quality of life (Between-group differences: week 3, 3.5%, P < 0.05; week 4, 4.6%, P < 0.001; week 5, 5.6%, P < 0.001). CONCLUSIONS: The 3-week application of TEAS in patients with CRP receiving chronic opioid therapy resulted in a statistically significant reduction in pain scores, but the observed reduction was of uncertain clinical significance. The prolonged analgesic effect of TEAS was not confirmed in this trial. CLINICALTRIAL: GOV: ChiCTR-TRC-13003803.

Can Electroacupuncture Be Useful in Opioid-Induced Hyperalgesia? A Case Report.

Opioid-induced hyperalgesia (OIH) is characterized by a paradoxical increase in pain sensitivity following opioid exposure. Although animal models indicate that electroacupuncture (EA) is effective against pain sensitization, there are no reports of its clinical application in OIH treatment. This case report involves an adult patient with osteomalacia complicated by multiple vertebral fragility fractures. The patient developed OIH following the use of oxycodone to treat severe disabling lower back pain that was refractory to nonsteroidal anti-inflammatory drugs. After hospitalization and treatment with low EA-frequency (2-10 Hz) sessions, the patient exhibited significant pain reduction and functional recovery after the first session, which was accompanied by steady progressive improvement as the treatment continued. This case report illustrates the clinical efficacy of EA in OIH treatment and indicates that EA, which has multiple modes of action on the neurobiology of chronic pain, has potential applications in the management of complex and difficult-to-manage conditions, such as OIH.

Analgesic effects of perioperative acupuncture methods: A narrative review.

Postoperative pain occurs immediately after surgery. The most common perioperative analgesic methods are nerve block, patient-controlled intravenous analgesia, and patient-controlled epidural analgesia. However, overuse of opioid analgesics can cause many adverse reactions including excessive sedation, respiratory inhibition, postoperative nausea, and vomiting. In recent years, many clinical trials have shown that perioperative acupuncture has unique advantages in patients. Perioperative acupuncture can relieve intraoperative pain, improve postoperative pain management, reduce postoperative nausea and vomiting, and shorten the length of hospital stay. This study aimed to confirm the analgesic effect of perioperative acupuncture by reviewing studies on the different methods of perioperative acupuncture and their analgesic effects. The cited literature was searched in English and Chinese from PubMed, China National Knowledge Infrastructure, and Wanfang data, using the following keywords: "perioperative pain," "acupuncture," "electroacupuncture," and "perioperative analgesia." Studies published from 2005 to 2023 were included. All retrieved papers were read in detail. Perioperative acupuncture has benefits in reducing postoperative pain and opioid need. Although analgesic drugs are still the primary means of postoperative pain control, acupuncture provides a safe analgesic supplement or alternative. This review aimed to assist practitioners in choosing appropriate perioperative acupuncture methods by summarizing the recent literature on the role of different acupuncture approaches for perioperative pain management.

From Plant to Chemistry: Sources of Active Opioid Antinociceptive Principles for Medicinal Chemistry and Drug Design.

Pain continues to be an enormous global health challenge, with millions of new untreated or inadequately treated patients reported annually. With respect to current clinical applications, opioids remain the mainstay for the treatment of pain, although they are often associated with serious side effects. To optimize their tolerability profiles, medicinal chemistry continues to study novel ligands and innovative approaches. Among them, natural products are known to be a rich source of lead compounds for drug discovery, and they hold potential for pain management. Traditional medicine has had a long history in clinical practice due to the fact that nature provides a rich source of active principles. For instance, opium had been used for pain management until the 19th century when its individual components, such as morphine, were purified and identified. In this review article, we conducted a literature survey aimed at identifying natural products interacting either directly with opioid receptors or indirectly through other mechanisms controlling opioid receptor signaling, whose structures could be interesting from a drug design perspective.

The Role of Adverse Childhood Experiences on People in Opiate Agonist Treatment: The Importance of Feeling Unloved.

INTRODUCTION: Adults in opiate agonist treatment (OAT) often have a background of adverse childhood experiences (ACEs) and are more likely to be exposed to a variety of risks that may trigger post-traumatic stress disorder (PTSD). Summative ACE scores are often used to identify individuals at risk of PTSD and continued substance use. What has not been addressed is whether specific ACE factors are exerting a greater influence on the individual. This study investigated whether specific ACEs predicted PTSD, and current continued substance use among adults in long-term OAT. METHODS: An analysis of data that were collected at the follow-up stage of a study among 131 adults who attended OAT was conducted. Participants attended one of six OAT settings, covering 45% (n = 890) of clients in a defined area of Dublin, Ireland in 2017. Interviews were conducted with 104 participants, 66 males (63%) and 38 females (37%), with an average age of 43 years (SD = 7.4). The Adverse Childhood Questionnaire (ACQ); PTSD checklist (PCL-5); heroin; tranquilliser; cannabis; alcohol; and cocaine used in the previous 28 days were measured using the quantity used score within the Opiate Treatment Index. Socio-demographics and age of first use of these four substances were also collected. The analysis has focussed on relating ACEs to PTSD, age of first drugs use, and current drug use of the participants. RESULTS: Bivariate analysis showed that the summative ACQ score was significantly correlated with age of first opiate use (p = 0.004). Multiple regression analysis showed that the summative ACQ score and tranquilliser use predicted higher levels of PTSD (R2 = 0.50). Four specific ACEs predicted 54% of the variance in PTSD, these were feeling unloved (ß = 0.328) living with a household member who had a problem with alcohol or used illicit street drugs (ß = 0.280); verbal abuse (ß = 0.219); and living with a person who had a mental illness (ß = 0.197). CONCLUSIONS: While a summation of all ten ACEs predicted higher levels of PTSD, the factor "feeling unloved" as a child provided the single strongest predictor and may represent an overarching risk of PTSD and continued substance use in later life among adults in treatment for an opiate use disorder.

Combating the Opioid Crisis and Its National Security Threat Through CReDO: A Multidisciplinary Solution With Disaster Medicine Implications.

For the first time in history, the United States surpassed 100 000 overdose-related deaths in a 12-month period, driven by synthetic opioids such as fentanyl. Also, for the first time, potential chemical weapons are readily available on the streets and the dark web. Opioids represent a rare trifecta, used for licit pain management, as an illicit drug of abuse, and with potential use as a weapon of terror. Community-based Response to Drug Overdose (CReDO) is an initiative to unite agencies, disciplines, government, and private partners in 1 coordinated opioid emergencies response plan under nationwide standards, and can be integrated into the disaster medicine discipline due to the risk of mass casualty incidents involving fentanyl or its derivatives. Attention to the opioid crisis through CReDO will save lives by promoting information sharing between disciplines, shortened response time to overdose clusters, community collaboration to identify criminal distribution networks, and holistic approaches to addiction.

Characteristics of patients undergoing medication-assisted -treatment for opioid use disorder and their interest in Tai Chi practice.

OBJECTIVES: (1) To explore the characteristics of patients with opioid use disorder (OUD) maintained on either methadone or buprenorphine and (2) to determine the relative acceptability of integrating Tai Chi (TC) practice into an ongoing medication-assisted treatment for opioid use disorder (MOUD) program. DESIGN: Survey study. SETTING: The University of Arkansas for Medical Sciences Center for Addiction Services and Treatment Program. PATIENTS: 97 patients receiving MOUD treatment. MAIN OUTCOMES: Drug use history, treatment status, physical limitation, mental health, pain, and whether participants were interested in using TC to improve health outcomes. RESULTS: At least 30.9 percent of the sample reported moderate or higher level of limitation in performing rigorous physical activities, pain intensity, and pain interference. Between 37.1 and 61.5 percent of the sample reported various psychiatric symptoms. Methadone patients reported higher levels of physical limitations, especially in rigorous activities (p = .012), climbing several flights of stairs (p = .001), and walking more than a mile (p = .011), but similar levels of pain (ps = .664-.689) and psychiatric symptoms (ps = .262-.879) relative to buprenorphine patients. At least 40.2 percent of participants expressed moderate or higher level of interest in TC for improving health outcomes, with methadone patients more interested in participating to ease mental and sleep problems (p = .005) and improve physical fitness (p = .015) compared to buprenorphine patients. CONCLUSIONS: High prevalence of physical limitation, pain, and psychiatric comorbidities were found in OUD patients. Since patients were interested in TC to improve their health outcomes, this low-cost intervention, if proven effective, can be integrated into ongoing MOUD programs to improve health in this population.

"I Just Don't Feel Heard": A Case Study on Opioid Use Disorder and Pain Management.

The nation's opioid epidemic requires a paradigm shift in the way patients with co-occurring opioid use disorder are treated during episodes of acute pain. Patients are often introduced to prescription opioids after an extremity fracture or sprain or resulting from musculoskeletal back, abdominal, or dental pain. Opioid naive patients who receive their first opioid prescription on discharge from the emergency department may be more likely to develop chronic opioid use compared to patients receiving non-opioid pain medications. This case report will highlight one patient's journey including initial prescription opioid use, escalation into illicit opioids, entry to a recovery and treatment program, discussions with her physician about alternative therapies, and barriers to satisfactory pain relief. A shared decision-making model will be explored.

Poppy Seeds Signal Limitations of Urine Drug Testing Protocols.

Appropriate care for patients with chronic pain is complex, requiring a thoughtful and holistic approach to pharmacologic intervention, as well as appropriate monitoring when opioids are employed as part of a multimodal regimen. The urine drug test has become an expected standard when longterm opioids are prescribed, but it should be remembered that this test is not intended to be punitive. It is ordered to promote patient safety (Dowell et al., 2022). Recent literature and events surrounding the effect of poppy seeds on urine drug test results have drawn attention to the risks of misinterpreting this test (Bloch, 2023; Lewis et al., 2021; Reisfield et al., 2023; Temple, 2023). Misinterpretation of urine drug tests creates a potential for unfounded accusations from health care workers toward patients, thus, undermining therapeutic relationships and intensifying stigma. Such circumstances may also preclude chances to offer patients needed interventions. Therefore, a valuable opportunity exists for nurses to mitigate untoward consequences by developing a robust understanding of urine drug testing, destigmatizing chronic pain and opioid use, advocating for patients, and enacting change at both an individual and a systems-level.

Acupuncture for protracted opioid abstinence syndrome: study protocol for a systematic review and meta-analysis.

INTRODUCTION: Protracted opioid abstinence syndrome (POAS) refers to a series of physical discomforts and neuropsychiatric symptoms after discontinuation of opioid-type substances for a certain amount of time and is one of the main causes of relapse. Studies have shown that acupuncture is effective in the treatment of POAS. We plan to conduct this systematic review and meta-analysis to assess the efficacy and safety of acupuncture for POAS. METHODS AND ANALYSIS: A comprehensive search of studies will be carried out in the following databases from inception to 31 January 2023: Web of Science, Embase, PubMed, Chinese Biology Medicine, China National Knowledge Infrastructure, Wan Fang Database and Chinese Scientific Journal Database (VIP). WHO International Clinical Trials Registry Platform, ClinicalTrials.gov and Chinese Clinical Trial Registry will also be searched for ongoing relevant trials, and 'grey literatures' will be identified from GreyNet International, OpenGrey and Google Scholar. Randomised controlled trials regarding acupuncture therapy for treatment of POAS will be included. The primary outcome is the severity of protracted withdrawal symptoms. Two reviewers will screen studies using the inclusion criteria, extract data and assess the risk of bias, respectively. The quality of evidence will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation. Data synthesis will be performed using RevMan V.5.4.1. ETHICS AND DISSEMINATION: This study will not invade patients' personal privacy, and so ethical review is not required. The results will be disseminated in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42022382978.

Cannabis-based medicines and medical cannabis for adults with cancer pain.

BACKGROUND: Pain is a common symptom in people with cancer; 30% to 50% of people with cancer will experience moderate-to-severe pain. This can have a major negative impact on their quality of life. Opioid (morphine-like) medications are commonly used to treat moderate or severe cancer pain, and are recommended for this purpose in the World Health Organization (WHO) pain treatment ladder. Pain is not sufficiently relieved by opioid medications in 10% to 15% of people with cancer. In people with insufficient relief of cancer pain, new analgesics are needed to effectively and safely supplement or replace opioids. OBJECTIVES: To evaluate the benefits and harms of cannabis-based medicines, including medical cannabis, for treating pain and other symptoms in adults with cancer compared to placebo or any other established analgesic for cancer pain. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 26 January 2023. SELECTION CRITERIA: We selected double-blind randomised, controlled trials (RCT) of medical cannabis, plant-derived and synthetic cannabis-based medicines against placebo or any other active treatment for cancer pain in adults, with any treatment duration and at least 10 participants per treatment arm. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. The primary outcomes were 1. proportions of participants reporting no worse than mild pain; 2. Patient Global Impression of Change (PGIC) of much improved or very much improved and 3. withdrawals due to adverse events. Secondary outcomes were 4. number of participants who reported pain relief of 30% or greater and overall opioid use reduced or stable; 5. number of participants who reported pain relief of 30% or greater, or 50% or greater; 6. pain intensity; 7. sleep problems; 8. depression and anxiety; 9. daily maintenance and breakthrough opioid dosage; 10. dropouts due to lack of efficacy; 11. all central nervous system adverse events. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We identified 14 studies involving 1823 participants. No study assessed the proportions of participants reporting no worse than mild pain on treatment by 14 days after start of treatment. We found five RCTs assessing oromucosal nabiximols (tetrahydrocannabinol (THC) and cannabidiol (CBD)) or THC alone involving 1539 participants with moderate or severe pain despite opioid therapy. The double-blind periods of the RCTs ranged between two and five weeks. Four studies with a parallel design and 1333 participants were available for meta-analysis. There was moderate-certainty evidence that there was no clinically relevant benefit for proportions of PGIC much or very much improved (risk difference (RD) 0.06, 95% confidence interval (CI) 0.01 to 0.12; number needed to treat for an additional beneficial outcome (NNTB) 16, 95% CI 8 to 100). There was moderate-certainty evidence for no clinically relevant difference in the proportion of withdrawals due to adverse events (RD 0.04, 95% CI 0 to 0.08; number needed to treat for an additional harmful outcome (NNTH) 25, 95% CI 16 to endless). There was moderate-certainty evidence for no difference between nabiximols or THC and placebo in the frequency of serious adverse events (RD 0.02, 95% CI -0.03 to 0.07). There was moderate-certainty evidence that nabiximols and THC used as add-on treatment for opioid-refractory cancer pain did not differ from placebo in reducing mean pain intensity (standardised mean difference (SMD) -0.19, 95% CI -0.40 to 0.02). There was low-certainty evidence that a synthetic THC analogue (nabilone) delivered over eight weeks was not superior to placebo in reducing pain associated with chemotherapy or radiochemotherapy in people with head and neck cancer and non-small cell lung cancer (2 studies, 89 participants, qualitative analysis). Analyses of tolerability and safety were not possible for these studies. There was low-certainty evidence that synthetic THC analogues were superior to placebo (SMD -0.98, 95% CI -1.36 to -0.60), but not superior to low-dose codeine (SMD 0.03, 95% CI -0.25 to 0.32; 5 single-dose trials; 126 participants) in reducing moderate-to-severe cancer pain after cessation of previous analgesic treatment for three to four and a half hours (2 single-dose trials; 66 participants). Analyses of tolerability and safety were not possible for these studies. There was low-certainty evidence that CBD oil did not add value to specialist palliative care alone in the reduction of pain intensity in people with advanced cancer. There was no difference in the number of dropouts due to adverse events and serious adverse events (1 study, 144 participants, qualitative analysis). We found no studies using herbal cannabis. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that oromucosal nabiximols and THC are ineffective in relieving moderate-to-severe opioid-refractory cancer pain. There is low-certainty evidence that nabilone is ineffective in reducing pain associated with (radio-) chemotherapy in people with head and neck cancer and non-small cell lung cancer. There is low-certainty evidence that a single dose of synthetic THC analogues is not superior to a single low-dose morphine equivalent in reducing moderate-to-severe cancer pain. There is low-certainty evidence that CBD does not add value to specialist palliative care alone in the reduction of pain in people with advanced cancer.

ANTECEDENTES: El dolor es un síntoma común en las personas con cáncer; entre el 30% y el 50% de las personas con cáncer experimentarán dolor de moderado a intenso. Esto puede tener un gran impacto negativo en su calidad de vida. Los fármacos opiáceos (similares a la morfina) se utilizan habitualmente para tratar el dolor por cáncer moderado o intenso, y se recomiendan para este propósito en la escala de tratamiento del dolor de la Organización Mundial de la Salud (OMS). El dolor no se alivia lo suficiente con los medicamentos opiáceos en el 10% al 15% de las personas con cáncer. En las personas con un alivio insuficiente del dolor por cáncer, se necesitan nuevos analgésicos que complementen o sustituyan de forma eficaz y segura a los opiáceos. OBJETIVOS: Evaluar los efectos beneficiosos y perjudiciales de los medicamentos con cannabis, incluido el cannabis medicinal, para tratar el dolor y otros síntomas en adultos con cáncer en comparación con placebo o cualquier otro analgésico establecido para el dolor por cáncer. MÉTODOS DE BÚSQUEDA: Se utilizaron los métodos exhaustivos estándar de búsqueda de Cochrane. La última fecha de búsqueda fue el 26 de enero de 2023. CRITERIOS DE SELECCIÓN: Se seleccionaron los ensayos controlados aleatorizados (ECA) doble ciego de cannabis medicinal, medicamentos derivados de plantas y sintéticos con cannabis versus placebo o cualquier otro tratamiento activo para el dolor por cáncer en adultos, con cualquier duración del tratamiento y al menos 10 participantes por grupo de tratamiento. OBTENCIÓN Y ANÁLISIS DE LOS DATOS: Se utilizaron los métodos estándar de Cochrane. Los desenlaces principales fueron los siguientes: 1. proporción de participantes que declararon dolor leve; 2. Patient Global Impression of Change (PGIC) de mucha o muchísima mejoría y 3. retiros debido a eventos adversos. Los desenlaces secundarios fueron 4. número de participantes que declararon un alivio del dolor del 30% o superior y un consumo general de opiáceos reducido o estable; 5. número de participantes que declararon un alivio del dolor del 30% o superior, o del 50% o superior; 6. intensidad del dolor; 7. problemas de sueño; 8. depresión y ansiedad; 9. dosis diaria de opiáceos de mantenimiento y de inicio; 10. abandonos por falta de eficacia; 11. todos los eventos adversos del sistema nervioso central. Se utilizó el método GRADE para evaluar la calidad de la evidencia de cada desenlace. RESULTADOS PRINCIPALES: Se identificaron 14 estudios con 1823 participantes. Ningún estudio evaluó las proporciones de participantes que declararon un dolor no peor que leve a los 14 días de inicio del tratamiento. Se encontraron cinco ECA que evaluaron nabiximoles oromucosos (tetrahidrocannabinol [THC] y cannabidiol [CBD]) o THC solo, con 1539 participantes con dolor moderado o intenso a pesar del tratamiento con opiáceos. Los periodos doble ciego de los ECA variaron entre dos y cinco semanas. Para el metanálisis se dispuso de cuatro estudios con un diseño paralelo y 1333 participantes. Hubo evidencia de certeza moderada de que no hubo efectos beneficiosos clínicamente relevantes en las proporciones de PGIC de mucha o muchísima mejoría (diferencia de riesgos [DR] 0,06; intervalo de confianza [IC] del 95%: 0,01 a 0,12; número necesario a tratar para lograr un resultado beneficioso adicional [NNTB] 16; IC del 95%: 8 a 100). Hubo evidencia de certeza moderada de que no hubo diferencias clínicamente relevantes en la proporción de retiros debido a eventos adversos (DR 0,04; IC del 95%: 0 a 0,08; número necesario a tratar para lograr un desenlace perjudicial adicional [NNTD] 25; IC del 95%: 16 a infinito). Hubo evidencia de certeza moderada de que no hubo diferencias entre nabiximols o THC y placebo en la frecuencia de eventos adversos graves (DR 0,02; IC del 95%: ­0,03 a 0,07). Hubo evidencia de certeza moderada de que los nabiximoles y el THC utilizados como tratamiento complementario para el dolor por cáncer refractario a los opiáceos no difirieron del placebo en cuanto a la reducción de la intensidad media del dolor (diferencia de medias estandarizada [DME] ­0,19; IC del 95%: ­0,40 a 0,02). Hubo evidencia de certeza baja de que un análogo sintético del THC (nabilona) administrado durante ocho semanas no fue superior a placebo para reducir el dolor asociado con la quimioterapia o la radioquimioterapia en personas con cáncer de cabeza y cuello y cáncer de pulmón de células no pequeñas (dos estudios, 89 participantes, análisis cualitativo). En estos estudios no fue posible realizar análisis de tolerabilidad y seguridad. Hubo evidencia de certeza baja de que los análogos sintéticos del THC fueron superiores a placebo (DME ­0,98; IC del 95%: ­1,36 a ­0,60), pero no superiores a la codeína en dosis bajas (DME 0,03; IC del 95%: ­0,25 a 0,32; cinco ensayos de dosis única; 126 participantes) en cuanto a la reducción del dolor moderado a intenso por cáncer después de la interrupción del tratamiento analgésico previo durante tres a cuatro horas y media (dos ensayos de dosis única; 66 participantes). En estos estudios no fue posible realizar análisis de tolerabilidad y seguridad. Hubo evidencia de certeza baja de que el aceite de CBD no agregó valor a los cuidados paliativos especializados solos en la reducción de la intensidad del dolor en personas con cáncer avanzado. No hubo diferencias en el número de abandonos debido a eventos adversos ni eventos adversos graves (un estudio, 144 participantes, análisis cualitativo). No se encontraron estudios que utilizaran la planta de cannabis. CONCLUSIONES DE LOS AUTORES: Existe evidencia de certeza moderada de que los nabiximoles y el THC por vía oromucosa no son efectivos para aliviar el dolor de moderado a intenso por cáncer refractario a los opiáceos. Hay evidencia de certeza baja de que la nabilona no es efectiva para reducir el dolor asociado con la radio­quimioterapia en personas con cáncer de cabeza y cuello y cáncer de pulmón de células no pequeñas. Hay evidencia de certeza baja de que una dosis única de análogos sintéticos del THC no es superior a una dosis única baja equivalente de morfina para reducir el dolor moderado a intenso por cáncer. Hay evidencia de certeza baja de que el CBD no aporta valor a los cuidados paliativos especializados solos en la reducción del dolor en personas con cáncer avanzado.

Molecular and Epigenetic Aspects of Opioid Receptors in Drug Addiction and Pain Management in Sport.

Opioids are substances derived from opium (natural opioids). In its raw state, opium is a gummy latex extracted from Papaver somniferum. The use of opioids and their negative health consequences among people who use drugs have been studied. Today, opioids are still the most commonly used and effective analgesic treatments for severe pain, but their use and abuse causes detrimental side effects for health, including addiction, thus impacting the user's quality of life and causing overdose. The mesocorticolimbic dopaminergic circuitry represents the brain circuit mediating both natural rewards and the rewarding aspects of nearly all drugs of abuse, including opioids. Hence, understanding how opioids affect the function of dopaminergic circuitry may be useful for better knowledge of the process and to develop effective therapeutic strategies in addiction. The aim of this review was to summarize the main features of opioids and opioid receptors and focus on the molecular and upcoming epigenetic mechanisms leading to opioid addiction. Since synthetic opioids can be effective for pain management, their ability to induce addiction in athletes, with the risk of incurring doping, is also discussed.

CYX-5, a G-protein biassed MOP receptor agonist, DOP receptor antagonist and KOP receptor agonist, evokes constipation but not respiratory depression relative to morphine in rats.

BACKGROUND: Strong opioid analgesics such as morphine alleviate moderate to severe acute nociceptive pain (e.g. post-surgical or post-trauma pain) as well as chronic cancer pain. However, they evoke many adverse effects and so there is an unmet need for opioid analgesics with improved tolerability. Recently, a prominent hypothesis has been that opioid-related adverse effects are mediated by ß-arrestin2 recruitment at the µ-opioid (MOP) receptor and this stimulated research on discovery of G-protein biassed opioid analgesics. In other efforts, opioids with MOP agonist and δ-opioid (DOP) receptor antagonist profiles are promising for reducing side effects c.f. morphine. Herein, we report on the in vivo pharmacology of a novel opioid peptide (CYX-5) that is a G-protein biassed MOP receptor agonist, DOP receptor antagonist and kappa opioid (KOP) receptor agonist. METHODS: Male Sprague-Dawley received intracerebroventricular bolus doses of CYX-5 (3, 10, 20 nmol), morphine (100 nmol) or vehicle, and antinociception (tail flick) was assessed relative to constipation (charcoal meal and castor oil-induced diarrhoea tests) and respiratory depression (whole body plethysmography). RESULTS: CYX-5 evoked naloxone-sensitive, moderate antinociception, at the highest dose tested. Although CYX-5 did not inhibit gastrointestinal motility, it reduced stool output markedly in the castor oil-induced diarrhoea test. In contrast to morphine that evoked respiratory depression, CYX-5 increased tidal volume, thereby stimulating respiration. CONCLUSION: Despite its lack of recruitment of ß-arrestin2 at MOP, DOP and KOP receptors, CYX-5 evoked constipation, implicating a mechanism other than ß-arrestin2 recruitment at MOP, DOP and KOP receptors, mediating constipation evoked by CYX-5 and potentially other opioid ligands.