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Consuming opioids for nonmedical reasons has occurred for centuries. Although epidemiologic research on opioid misuse can be difficult, we do know that it differs from what has been witnessed in the past. The types of opioids, the methods in which they are consumed and the geographical locations most affected are just some of the characteristics that have changed over time. Efforts are currently underway to predict the course of the opioid epidemic through the use of mathematical modeling and computer programming.
The opioid crisis continues to affect many areas worldwide, raising questions regarding prescribing indications. There is no consensus on negotiating the need for pain relief and the potential for medically prescribed opioid-related harm/addiction. These issues present an enormous educational challenge to physicians in training, particularly those whose mandate is to understand and respond to varying forms of pain. This article examines the perspectives and educational challenges faced by two psychiatry residents from different parts of the globe during the crisis. Is the educational experience of future psychiatrists sufficient to prepare them for the responsibilities that lie ahead?
It is important to study the corticosteroid receptors hypothesis of Depression.
Objectives
The goal of current study was - to test the influence of the opioid, adrenergic and benzodiazepine drugs on the immunosuppressive levels of leukocyte pyruvat dehydrogenase activity (LPDG) during the DST in patients with Major Depression and Anxiety Disorder.
Methods
Patients. 40 male/ mean age, 33,1+3,2 years/ and 20 premenopausal female /35,1+1,6 years/ patients with Primary Major Depressive Episode were studied. All patients were diagnosed by a psychologist and fulfilled DSM- IV criteria for Major Depressive Episode. The DST was conducted to 60 patients with Primary Depressive Episode and 30 healthy subjects
Results
In the cases of Primary Major Depressive Episode in separation with an Anxiety Disorder after TRAMADOL and DIASEPAM administration activity of LPDG increased more than 25%. Tramadol of a 50 mg dose and Diasepam of a 10 mg dose had a higher immunosuppressive effect than L-DOPA (0,5 g) on alteration of LPDG activity (more than 5 mmol/l/hour, p <0,05/.
Conclusions
TRAMADOL immunosuppresssive action was higher than L-DOPA and DIASEPAM on LPDG activity in patients with an Anxiety Disorder and Major Depression. Diasepam immunosuppressive action did not correlate with positive dynamics of LPDG levels of DST in patients with Anxiety Disorder (after the 4-5 th week of Diasepam treatment). From other side, mechanism of L-DOPA action on corticosteroid receptors stimulated LPDG-activity (L-DOPA therapeutic effective dose-3 g). It means that opiate, adrenergic and benzodiazepine receptors are interactiing with each other and influencing on the corticosteroid receptors in different ways during immunosuppression.
Addiction is a chronic yet treatable disorder. Patterns of addiction, whether substance related or behavioural, vary among countries and regions. Addiction medicine practice and approaches used in management are not only different from one country to another but are influenced by other factors, including environmental ones. The COVID-19 pandemic is one of the major environmental changes that had an impact on addiction. In this editorial, light will be shed on three articles covering recent updates in addiction medicine, ranging from types of substances and service provision to inclusion of gaming disorder in ICD-11.
As defined by the World Health Organization, the Eastern Mediterranean Region (EMR), given its special geopolitical situation and internal/external conflicts, faces an increase in illegal activities such as drug production and trafficking, highlighting the need for a comprehensive understanding of the substance use situation. On the basis of a review of published papers between 2015 and 2021 we briefly review substance use in the EMR with special focus on the emerging drugs pertinent to this region, namely tramadol, captagon and khat.
Tramadol is used worldwide and is listed in many medical guidelines to treat both acute and chronic pains. There is a growing evidence of abuse of tramadol in some African and West Asian countries. Tramadol has some side effects. The present study designed to follow up the treatment of the cellular responses which might be induced in the kidney of tramadol mice. Treated mice received daily injection of tramadol dose (125 μg/100 g b.wt) for 20 and 40 days. Other mice received tramadol for 40 days and then were divided into three groups: the first received distilled water, the second received Lagenaria siceraria, and the third received melatonin daily for 40 days. Both the daily injection of tramadol for 20 and 40 days resulted in radical, extensive, and severe alterations in the normal histological architecture of the kidney. Treatment with Lagenaria siceraria or melatonin after tramadol administration for a long-term, markedly changed the collagen content and other chemical components, that may reach nearly normal levels. Such findings propose that although tramadol has many cytological and histopathological side effects on the kidneys of male mice, the treatments via Lagenaria siceraria and melatonin have effective therapeutic impacts on the tramadol side effects.
Poor analgesic control diminishes a patient’s quality of life and may slow down hospital recovery. The reader is introduced to the basic concepts of analgesia, including the WHO Pain Ladder, and some of the most commonly used analgesics, along with their indications, side effects and relative contraindications. Opioids are also described, and new prescribers are provided with conversion tables for the most commonly used preparations, including transdermal patches.
Tramadol is a centrally acting analgesic drug, used for the management of moderate to severe pain in a variety of diseases. The long-term use of tramadol can induce endocrinopathy. This study aimed to evaluate the effect of tramadol dependence on the adrenal cortex and the effect of its withdrawal. Thirty adult male rats were divided into three experimental groups: the control group, the tramadol-dependent group that received increasing therapeutic doses of tramadol orally for 1 month, and the recovery group that received tramadol in a dose and duration similar to the previous group followed by a withdrawal period for another month. Specimens from the adrenal cortex were processed for histological, immunohistochemical, enzyme assay, and quantitative real-time PCR (RT-qPCR) studies. Tramadol induced a significant increase in malondialdehyde level and a significant decrease in the levels of glutathione peroxidase and superoxide dismutase. A significant decrease in the levels of adrenocorticotrophic hormones, aldosterone, cortisol, corticosterone, and dehydroepiandrosterone sulfate was also detected. Severe histopathological changes in the adrenal cortex were demonstrated in the form of disturbed architecture, swollen cells, and shrunken cells with pyknotic nuclei. Inflammatory cellular infiltration and variable-sized homogenized areas were also detected. A significant increase in P53 and Bax immunoreaction was detected and confirmed by RT-qPCR. The ultrastructural examination showed irregular, shrunken adrenocorticocytes with dense nuclei. Dilated smooth endoplasmic reticulum, mitochondria with disrupted cristae, and numerous coalesced lipid droplets were also demonstrated. All these changes started to return to normal after the withdrawal of tramadol. Thus, it was confirmed that the long-term use of tramadol can induce severe adrenal changes with subsequent insufficiency.
Chronic opioid exposure is common world-wide, but behavioural performance remains under-investigated. This study aimed to investigate visuospatial memory performance in opioid-exposed and dependent clinical populations and its associations with measures of intelligence and cognitive impulsivity.
Methods
We recruited 109 participants: (i) patients with a history of opioid dependence due to chronic heroin use (n = 24), (ii) heroin users stabilised on methadone maintenance treatment (n = 29), (iii) participants with a history of chronic pain and prescribed tramadol and codeine (n = 28) and (iv) healthy controls (n = 28). The neuropsychological tasks from the Cambridge Neuropsychological Test Automated Battery included the Delayed Matching to Sample (DMS), Pattern Recognition Memory, Spatial Recognition Memory, Paired Associate Learning, Spatial Span Task, Spatial Working Memory and Cambridge Gambling Task. Pre-morbid general intelligence was assessed using the National Adult Reading Test.
Results
As hypothesised, this study identified the differential effects of chronic heroin and methadone exposures on neuropsychological measures of visuospatial memory (p < 0.01) that were independent of injecting behaviour and dependence status. The study also identified an improvement in DMS performance (specifically at longer delays) when the methadone group was compared with the heroin group and also when the heroin group was stabilised onto methadone. Results identified differential effects of chronic heroin and methadone exposures on various neuropsychological measures of visuospatial memory independently from addiction severity measures, such as injecting behaviour and dependence status.
Tramadol hydrochloride (HCl) is a centrally acting synthetic opioid analgesic. Psychotic symptoms are relatively rare in reported adverse events. Here, we report a patient who presented with tramadol-related psychotic symptoms.
Case
A 59-year-old female had underlying bipolar I disorder and received lithium treatment with stable affective status. 1 month before hospitalisation, she had been taking tramadol HCl/acetaminophen for joint pain. She then developed obvious persecutory delusion. However, her clinical picture did not meet the criteria of any mood episode. After treatment of risperidone in addition to lithium, she was discharged without any psychotic symptom. She remained euthymic without any psychotic symptom on monotherapy of lithium (300 mg) three tablets once daily.
Conclusions
Tramadol HCl is commonly prescribed in clinical practice and psychotic symptoms related to it are uncommon. We should be careful about the rare but important adverse events while prescribing tramadol HCl.
This chapter focuses on the issues that arise when prescribing opioids and other controlled substances for chronic headache pain. The majority of headache patients who overuse or develop dependence on opioids and opioid-containing compounds suffer from migraine-type headaches. Tramadol withdrawal often includes symptoms not typically seen in pure opioid withdrawal, such as extreme anxiety, panic or paranoia, hallucinations, and feelings of numbness and tingling in extremities. Butorphanol, an opioid with partial mu-agonist effects, was first developed in injectable form and initially used in hospital settings mainly for post-operative and labor pain. The only barbiturate indicated specifically for the treatment of headache is butalbital, prescribed in the various combination medications. The care of cannabis-using patients may be managed best by coordinating their continuing headache care with an addiction specialist. It is well known that patients with physiologic dependence on caffeine routinely develop caffeine withdrawal headaches.
Several studies have reported the use of peritonsillar infiltrations of local anaesthetics and/or locally active analgesic drugs for the relief of post-tonsillectomy pain, with variable results in terms of quality and duration of analgesia. We aimed to compare the effects of peritonsillar infiltration of lidocaine versus tramadol versus placebo on post-tonsillectomy pain.
Methods:
Sixty patients over the age of 10 years undergoing bilateral elective tonsillectomy under general anaesthesia were randomised into three groups. The first group received peritonsillar infiltration of tramadol, the second 2 per cent lidocaine and the third normal saline. In all groups, peritonsillar infiltration was carried out after tonsillectomy but prior to tracheal extubation. Post-operative comparisons were made to assess the quality of pain control and the patients' analgesic requirements.
Results:
Peritonsillar infiltration of tramadol provided an analgesic effect comparable to that of lidocaine in the first 6 hours post-operation, as reflected by visual analogue scale pain scores and opioid requirements, which were lower compared with the placebo group.
Conclusion:
Peritonsillar infiltration of tramadol provided pain control in the first 6 hours post-tonsillectomy which was comparable to that of lidocaine.
This chapter discusses the importance of pain relief, source of pain, types and severity of pain and modalities of pain relief. Paracetamol is very useful for soft tissue pain and as an opioid sparing drug in more severe pain states. Non-steroidal anti-inflammatory drugs (NSAIDs) are powerful analgesics, particularly useful for bony pain. Tramadol is an atypical analgesic with antagonist actions at morphine receptors and inhibitory effects on the reuptake of serotonin and norepinephrine from the synaptic cleft. Potentiation of serotinergic neurons may be important in activating the descending pain control neuronal pathways. Opioids are the most potent analgesics widely available and form the basis of most critical care pain management treatments. The different opioids discussed in the chapter are: morphine, diamorphine, fentanyl, alfentanil, remifentanil, codeine, ketamine and nitrous oxide. Regional anaesthesia is commonly provided in conditions where the pain intensity is expected to resolve over time.
Although complete remission of symptoms is the goal of any depression treatment, many patients fail to attain or maintain a long-term, symptom-free status. The opioid system has been implicated in the aetiology of depression, and some preclinical and clinical data suggest that opioids possess a genuine antidepressant-like effect. This study aimed to investigate a potential antidepressant strategy combining different classes of monoaminergic compounds with the weak μ-opioid agonist codeine in the tail suspension test in mice, a paradigm aimed at screening potential antidepressants. The results showed that codeine produced an antidepressant-like effect when administered alone, that was effectively antagonized by the opioid antagonist naloxone. The combination of subeffective doses of codeine with the selective serotonin reuptake inhibitors (fluoxetine or citalopram) lead to an accentuated reduction in immobility time. In contrast, immobility time remained unchanged when codeine was combined with a noradrenaline reuptake inhibitor (desipramine) or with a noradrenaline/serotonin reuptake inhibitor (duloxetine). The immobility time also remained unchanged with the combination of subeffective doses of codeine plus (±)-tramadol (weak μ-opioid agonist with serotonin/noradrenaline reuptake inhibitor properties) or (−)-tramadol (noradrenaline reuptake inhibitor). Conversely, the combination with (+)-tramadol (μ-opioid agonist with serotonin reuptake inhibitor properties) produced a large decrease in the immobility time. All these combinations were without effects on motor behaviour in mice. These data support the hypothesis that a combination of classical serotonergic antidepressants and weak opioid receptor agonists may be a helpful new strategy in the treatment of refractory depression.
The serotonin syndrome is a potential side-effect of serotonin-enhancing drugs, including antidepressants such as selective serotonin reuptake inhibitors (SSRIs) and monoamine oxidase inhibitors (MAOIs). We recently reported a genetic mouse model for the serotonin syndrome, as serotonin transporter (SERT)-deficient mice have exaggerated serotonin syndrome behavioural responses to the MAOI tranylcypromine and the serotonin precursor 5-hydroxy-l-tryptophan (5-HTP). As numerous case reports implicate the atypical opioids tramadol and meperidine in the development of the human serotonin syndrome, we examined tramadol and meperidine as possible causative drugs in the rodent model of the serotonin syndrome in SERT wild-type (+/+), heterozygous (+/−) and knockout (−/−) mice. Comparisons were made with SERT mice treated with either vehicle or morphine, an opioid not implicated in the serotonin syndrome in humans. Here we show that tramadol and meperidine, but not morphine, induce serotonin syndrome-like behaviours in mice, and we show that this response is exaggerated in mice lacking one or two copies of SERT. The exaggerated response to tramadol in SERT−/− mice was blocked by pretreatment with the 5-HT1A antagonist WAY 100635. Further, we show that morphine-, meperidine- and tramadol-induced analgesia is markedly decreased in SERT−/− mice. These studies suggest that caution seems warranted in prescribing or not warning patients receiving SSRIs or MAOIs that dangerous side-effects may occur during concurrent use of tramadol and similar agents. These findings suggest that it is conceivable that there might be increased vulnerability in individuals with SERT polymorphisms that may reduce SERT by more than 50%, the level in SERT+/− mice.
We have investigated whether, after major abdominal surgery, the addition of remifentanil to tramadol for intravenous patient-controlled analgesia improved analgesia and lowered pain scores, compared to a patient-controlled analgesia containing only tramadol.
Methods
Sixty-two patients were allocated randomly to receive an intravenous patient-controlled analgesia with tramadol alone (T), or tramadol plus remifentanil (TR), in a double-blind randomized study. Whenever patients complained of pain, they were allowed to use bolus doses of tramadol (0.2 mg kg−1) or tramadol (0.2 mg kg−1) plus remifentanil (0.2 μg kg−1) mixture every 10 min without a time limit and background infusion. Discomfort, sedation, pain scores, total and bolus patient-controlled analgesia tramadol consumption, and side-effects were recorded for up to 24 h after the start of patient-controlled analgesia.
Results
Pain scores at rest were statistically significantly lower in the TR group at 6, 12 and 24 h than in T group (P < 0.05). Pain scores at movement and patient comfort scores were also found to be significantly lower in the TR group at 2, 6, 12 and 24 h than in the T group (P < 0.05). Although the TR group consumed less tramadol, there were no statistically significant differences in the cumulative tramadol consumptions between the groups at any time. However, the number of patients requiring rescue analgesia and average supplementary doses used was significantly higher in the T group than in the TR group (P < 0.05).
Conclusions
After major abdominal surgery, adding remifentanil (0.2 μg kg−1) to tramadol (0.2 mg kg−1), with 10-min lockout times, for patient-controlled analgesia offered better postoperative pain relief and patient comfort, without causing any sedation or respiratory depression.
Patients with odontogenic pain (OP) represent a broad spectrum of both disease etiology and severity. This chapter overviews the most important systemic, parenteral, and topical analgesic choices available to the acute care provider trying to relieve OP. NSAIDs are among the most widely used and well-studied drug classes used in management of acute and chronic OP, or odontalgia. Among the NSAIDs demonstrated to provide better pain relief than placebo is parenteral ketorolac. The mixed-mechanism drug tramadol provides pain relief that is partially mediated by opioid receptors. The supraperiosteal infiltration of local anesthetics usually provides suitable anesthesia when OP is emanating from a single maxillary tooth. Injection of local anesthetics is a legitimate, well-studied mechanism for providing relief of OP. In addition to its potential use in alveolar osteitis, benzocaine is efficacious in other causes of OP.
Postoperative shivering and pain are frequent problems in patients recovering from anaesthesia with particularly high incidences being observed after remifentanil–isoflurane-based general anaesthesia. The opioid tramadol is generally effective in preventing shivering and treating pain, but its effects are not characterized after remifentanil-based general anaesthesia. This randomized, placebo-controlled, double-blind study evaluated the effects of intraoperative intravenous tramadol on postoperative shivering and pain after remifentanil-based general anaesthesia.
Methods
After Ethics Committee approval, 60 patients scheduled for lumbar disc surgery were included. Surgery was performed under general anaesthesia (remifentanil, isoflurane). Patients were randomly assigned to receive 2 mg kg−1 tramadol in 30 mL 0.9% saline infused intravenously (n = 30) or 30 mL saline (n = 30) 45–30 min before skin closure. The following parameters were assessed every 10 min for 2 h: shivering, pain, postoperative nausea and vomiting, sedation, heart rate, non-invasive blood pressure and peripheral oxygen saturation. The primary outcome variable was the incidence of shivering during the first 2 postoperative hours. Secondary variables were: shivering intensity, pain, postoperative nausea and vomiting, sedation, heart rate, non-invasive blood pressure and peripheral oxygen saturation.
Results
Shivering was less frequent in patients treated with tramadol (20% vs. 70%, P = 0.0009) and was of lower intensity (severe shivering: 10% vs. 46.7%, P = 0.003). Pain scores were similar between the groups and all other secondary outcome variables failed to reveal significant differences.
Conclusions
Compared with placebo, intraoperative intravenous administration of 2 mg kg−1 tramadol reduces the incidence and extent of postoperative shivering without alterations in pain perception after lumbar disc surgery under remifentanil–isoflurane-based general anaesthesia.
The aim of this study was to compare the postoperative analgesic efficacy of intraperitoneal tramadol with intravenous tramadol or normal saline in patients undergoing laparoscopic cholecystectomy.
Methods
Sixty-one patients undergoing laparoscopic cholecystectomy were randomized to one of three groups in a double-blind manner via coded syringes. All patients received an intravenous and an intraperitoneal injection after installation of the pneumoperitoneum and again before removal of the trocars. In the control group, all injections were with normal saline. In the intravenous tramadol group, patients received intravenous tramadol 100 mg and intraperitoneal saline. In the intraperitoneal tramadol group, patients received intravenous saline and intraperitoneal tramadol 100 mg. All patients had a standard anaesthetic. Postoperative analgesia was with morphine. Postoperatively, numeric pain scores for parietal and visceral pain, 1 h and 24 h morphine consumption, and adverse effects were recorded.
Results
Parietal and visceral pain scores were lowest in the intravenous tramadol group during the first postoperative hour (P < 0.016 compared with control). The delay until the first analgesic administration was longest in the intravenous tramadol group (median 23 min, range 1–45), when compared with the intraperitoneal tramadol group (10, 1–120 min, P = 0.263) or with the control group (1, 1–30 min, P = 0.015). One-hour morphine consumption was significantly lower in the intravenous tramadol group (mean ± SD; 3.4 mg ± 2.5) and in the intraperitoneal tramadol group (4.4 ± 4.3 mg) compared with the control group (6 ± 2 mg) (P = 0.044). There was no difference between the three groups regarding pain scores, morphine consumption and incidence of shoulder pain or adverse effects at 24 h.
Conclusion
Intravenous tramadol provides superior postoperative analgesia in the early postoperative period after laparoscopic cholecystectomy compared with an equivalent dose of tramadol administered intraperitoneally and with normal saline in patients undergoing laparoscopic cholecystectomy.