Emerging trends in Abuse-Deterrent Formulations: Technological insights and Regulatory considerations

Background: Opioid medications are an integral part in the management of acute and chronic severe pain. However, non-medical practice of these prescription drug products is emerging as a serious public health problem. To control this opioid epidemic, USFDA is encouraging pharmaceutical companies to develop Abuse Deterrent Formulations (ADFs). Abuse Deterrent Formulations are much more difficult to manipulate and abuse when compared to their conventional formulations. This feature of ADFs is due to their ability to incumber extraction of active ingredients, to prevent administration through alternative routes and making abuse of altered product less rewarding. Objective: The main objective of this review is to abridge different ADFs and various laboratory-based in vitro manipulation and extraction studies, demonstrating that these approved ADFs have capabilities to deter abuse. Methods: The method includes collection of data from different search engines like PubMed, FDA guidance documents, ScienceDirect, Google Patents to get coverage of literature in order to get appropriate information regarding ADFs. Results: Various in vitro studies demonstrate that ADFs are effective in minimizing opioid drug abuse including opioid overdose. However, real impact of these ADFs on reducing the drug abuse can be concluded only after receiving the post marketing data. Conclusion: ADFs are embracing fundamentally different paradigm in management of severe pain. We believe that development of abuse deterrent technologies would shift the architype, deterring multipill abuse and can prove as a breakthrough strategy in controlling this opioid epidemic menace.

Undiagnosed Case of Klippel-Trenaunnay Syndrome Presenting as Extensive Heterotrophic Ossification and Flexion Deformity of Right Lower Limb Requiring Amputation : A Case Report

Klippel-Trenaunnay Syndrome is a rare disease characterized by a clinical triad of capillary malformation, soft tissue and bony hypertrophy, and atypical varicosity. This syndrome ranges from asymptomatic disease to life-threatening bleeding, embolism, and deformities. Management includes early diagnosis, prevention, and treatment of complications. We present a case of a 43-year-old male presenting with pain, swelling and deformity of the right leg for 30 years. On examination, diffusely enlarged tender right limb with several dark patchy discolorations, multiple tortuous vessels were found. Right leg X-ray showed heterotrophic ossification and distortion of ankle joint. Due to chronic severe pain, recurrent infection, contracture and flexion deformity of right leg, the patient underwent above knee amputation. This case focuses on the variable presentation and multiple problems faced by patients with Klippel-Trenaununay Syndrome as they get diagnosed late and shows the importance of high index of suspicion for early diagnosis and prevention of complications.

The risks of physicians’ conformism: reflections from the opioid overflow

Opioid-related mortality in adolescents is spreading in the US, with prescription opioids playing a crucial role in the development of addiction. We traced back to the process leading to the so called “opioid overflow”, trying to identify any modifiable attitude.Since the late 1990s, pain was labelled as the “fifth vital sign” and its proper management was prompted, encouraging the use of opioids for any pain scored at a Numerical Rating Scale (NRS) of 7 or higher. This assumption has some remarkable limitations. NRS is a proxy of pain severity in children, and pain measurement should be strengthened by a more comprehensive pain evaluation. Moreover, while remaining a fundamental therapeutic right of patients suffering postoperative or chronic severe pain, opioids show no evidence of superiority respect to non-opioid regimens in the management of pain from several acute conditions.Italy, as other European countries, is often reluctant to the use of opioids, even when highly recommendable, missing the opportunity of properly treating those selected patients with severe pain. Both attitudes can be viewed as the result of an extreme simplification of the complex process of pain evaluation and treatment, by means of a ‘one-size-fits-all’ approach.This highlights the need for a systematic and patient-tailored attitude to children in pain, avoiding applying guidelines without question. Good clinical practice must rely on guidelines, which, however, as often based on partial and insufficient data, can be questioned by emerging new evidence, and should not substitute our rational thinking, and capability to understand each patient, avoiding excessive conformism.

Epidural analgesia for intractable cancer pain - An old story used until now

Intractable cancer pain is a chronic severe pain, affecting patient’s quality of life and presents aheavy health, social and family problem in many countries. Different methods for pain relief are proposed by the WHO. Epidural analgesia with opioids is one of the proposed methods. Aim of the study was to determine the effects of morphine, fentanyl and butorphanol used for epidural analgesia in intractable pain and to comment our experiences over a five-year-period, with regard to its actuality nowadays. Material and methods: Retrospective longitudinal observational study was carried at the University Clinic for Anesthesiology, Reanimation and Intensive Care in Skopje, Macedonia, between 2005-2010 and evaluated in 2017-2018. A total of 116 patients suffering from intractable pain were enrolled in the study. Exclusion criteria were: infective and metastatic processes in the spine, allergy to opioids, psychological problems and language barrier. After the pretreatment evaluation of the pain, patients were randomly assigned to receive three different opioids through epidural catheter placed from Th8-10 or L2-3. Results: There were no differences in pretreatment pain scores between the three groups (p>0.05). A significant onset of analgesia after 15 minutes was found for butorphanol, 20 minutes for fentanyl and 30 minutes for morphine group (p<0.05). The duration of the pain relief of butorphanol vs. fentanyl vs. morphine was 6h vs. 8h vs. 24 hours respectively. Morphine had the longest duration of pain relief (p<0.05). Because of an increase in the pain threshold, the need of an increase of opioid doses was necessary. The most often patient’s reports of side effects were: itching, constipation, urine retention and bradypnea and there were no reports of nausea and vomiting. Conclusions: It was concluded that epidural analgesia with opioids is an effective and safe method for suppression of intractable pain. In spite of the other alternatives in treatment of cancer pain, epidural analgesia with opioids still has an eminent place and its use is a challenge for professionals

Chronic Severe Pain and Use of Prescription Pain Medications in Older Survivors of Hematologic Malignancies (HM) Several Years after Treatment with Blood or Marrow Transplantation (BMT): A Report from BMTSS

Background: BMT is increasingly offered to older patients with HM. The high burden of comorbidity in older BMT survivors places them at a higher risk for chronic severe pain - an issue that has not been comprehensively evaluated. We used BMTSS to investigate the prevalence and predictors of chronic severe pain several years after BMT. We examined the impact of pain on physical performance and frailty and also examined the relation between chronic severe pain and use of prescription pain medications and opioids in this population. Methods: The cohort included 601 HM patients who had received a BMT at age ≥60y at one of 3 transplant centers between 1974 and 2014 and had survived ≥2y after BMT; 183 unaffected siblings also participated. Self-reported domains included sociodemographics, chronic GvHD, physical performance, frailty, and medication use. Clinical information obtained from institutional databases included primary HM diagnosis, donor source, and conditioning regimen. Study participants completed a detailed questionnaire that examined pain in the following 3 domains: moderate-to-severe bodily pain, prolonged pain, and moderate-to-extreme pain interference; these 3 domains were used to create a composite variable, wherein presence of ≥1 domain was indicative of "chronic severe pain". An adjusted multivariable logistic regression model for chronic severe pain was used to compare BMT survivors to siblings. Analyses restricted to BMT survivors were stratified by donor type. Results: Survey participation rates were 62.7% and 60%, for the BMT survivors and siblings, respectively. Median age at study participation was 69.8y (61-89) for BMT survivors and 68.9y (65-80) for siblings. Median time from BMT was 5.0y (2-17) for BMT survivors. Chronic severe pain: Overall, 39.4% of the BMT survivors reported chronic severe pain; multivariable analysis revealed a 2.5-fold greater odds of BMT survivors reporting chronic severe pain (95%CI, 1.7-3.8, p <0.0001) when compared with siblings. Domain-specific prevalence and magnitude of risk of pain are shown in Fig 1. Among allogeneic BMT recipients, survivors with lower education (<high school: OR=5.2, 95%CI: 1.5-18.3, p=0.01; ref grp: >college) and lower income (<$50k: OR=6.0, 95%CI, 1.7-20.8, p=0.005; $50k-<$100k: OR=3.8, 95%CI, 1.3-11.4, p=0.02; ref group: ≥$100k) had higher odds of reporting chronic severe pain; presence of active chronic GvHD was associated with 2.3-fold higher odds, but did not reach statistical significance (p=0.1). Among autologous BMT recipients, lower income (<$50k: OR=2.2, 95%CI, 1.1-4.4, p=0.02) was associated with higher odds of reporting chronic severe pain. Pain and physical performance/frailty: Allogeneic and autologous BMT recipients with chronic severe pain were at a 2.7-fold (95%CI, 1.2-6.0, p=0.02) and 3.0-fold (95%CI, 1.9-4.9, p<0.0001) higher odds of reporting impaired physical performance, respectively, when compared to those without pain. Allogeneic and autologous BMT recipients with chronic severe pain were at 8.2-fold (95%CI, 2.4-27.6, p=0.0007) and 7.5-fold (95%CI, 3.3-16.8, p<0.0001) higher odds, respectively of having frailty when compared to those without pain. Use of prescription pain medications and opioids: Overall, 17.8% of BMT survivors reported using prescription pain medications, and 6.5% reported using opioids; those with chronic severe pain were at a 2.5-fold higher odds of using prescription pain meds (95%CI, 1.6-3.8, p<0.0001) and at a 6.0-fold higher odds of using opioids (95%CI, 2.8-12.9, p <0.0001), when compared with those without pain. Conclusions: Nearly 40% of older BMT survivors followed for a median of 5y after BMT, report chronic severe pain. BMT survivors are at a 2.5-fold higher odds of reporting chronic severe, life-interfering pain as compared with siblings. Chronic severe pain is associated with impaired physical performance and frailty. Finally, nearly 18% of long-term BMT survivors report use of prescription medications and 6.5% are using opioids. This study draws attention to the vulnerability of older BMT survivors and provides evidence for the need to develop effective strategies to address the underlying causes of pain. Disclosures No relevant conflicts of interest to declare.

Clinical study of pain after inguinal hernia repair

Background: Chronic severe pain following inguinal hernia repair is a significant post-operative problem. Pain is a complex study subject, mostly defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage.Methods: Patients undergoing elective inguinal hernioplasty in the Hospital from March 2016 to March 2017 were included in the study. Seventy-eight patients were present for follow up for a period of 6 months. Patients presenting with obstructed/strangulated inguinal hernia were excluded from study.Results: Majority of our patients were male 97.43% with mean age 49.1 years (range 16-78 years). Table 8 shows the VAS scores of patients at six months following surgery. When patients were divided into groups of mild (1-3), moderate (4-7), and severe pain (>7) on basis of VAS score, it was found that majority, 34.61%, had mild pain, 8.97% had moderate pain, and less than 1% had severe pain.Conclusions: In the present study, author found that chronic pain following inguinal hernia repair causes significant morbidity to patients and should not be ignored. All measures must be taken to suppress early postoperative pain and prevent complications as these lead to development of chronic pain.

Innovations in Pain Management: Morphine Combined with Omega-3 Fatty Acids

The treatment of acute and chronic severe pain remains a common major challenge faced by clinicians working with the general population, and even after the application of recent advances to treatments, there may still continue to be manifestations of adverse effects.Chronic pain affects the personal and social life of the patient, and often also their families. In some cases, after an acute pain the patient continues to experience chronic pain, which can be a result of diseases such as cancer.Morphine is recommended as the first choice opioid in the treatment of moderate to severe acute and chronic pain. However, the development of adverse effects and tolerance to the analgesic effects of morphine often leads to treatment discontinuation.The present work reviews the different pharmaceutical innovations reported concerning the use of morphine. First, its utilization as the first medication for the treatment of moderate to severe cancer pain and non-cancer pain in patients is evaluated, taking into account the most common complications and adverse effects. Next, strategies utilized to manage these side effects are considered, and we also summarize results using omega-3 fatty acids (eicosapentaenoic acid and docosahexaenoic acid) as a monotherapy or as an adjunct to morphine in the treatment of pain.

Patients with Pain During Pregnancy

Most women experience some degree of pain during pregnancy. Back pain occurs in about half of all pregnant women, with pain typically in the low back due to the physiologic changes in the body that occur with pregnancy, such as weight gain, changed center of gravity, increased ligament and joint laxity, and altered posture. Pelvic pain, leg cramps, and abdominal pain are all common among pregnant women. Many women who have pain during pregnancy are reluctant to use analgesics due to concerns about what the medications may do to their unborn child. Because of this, it is hypothesized that many women are either undertreated for pain or do not receive any treatment. Chronic, severe pain that is ineffectively treated is associated with hypertension, anxiety, and depression, all of which do not lead to a healthy pregnancy. A variety of interventional procedures are commonly performed during pregnancy that can safely alleviate pain. This review goes into detail about the types of pain treatments that are available to pregnant women and are safe and effective in alleviating pregnancy-related pain. Keywords: Pelvic pain, leg cramps, abdominal pain, hypertension, anxiety, depression, joint laxity, ligament laxity, back pain, analgesics, pregnancy