Antioxidants (selenium and garlic) alleviated the adverse effects of tramadol on the reproductive system and oxidative stress markers in male rabbits.

Tramadol has been used by millions of patients as an analgesic drug to relief the severe pain caused by cancers and other diseases. The current study aimed to investigate the protective effects of antioxidants (garlic and selenium) against the toxic effects of tramadol on semen characteristics, steroid hormones, the protein expressions of different cytochrome P450 isozymes [CYP 21A2, CYP 19, and 11A1], and on antioxidant enzyme activities in testes of rabbits. Western immunoblotting, spectrophotometric, and histological methods were used in this study. Tramadol (1.5 mg/kg body weight) was administered orally to male rabbits for up to three months (three times/week), and after pretreatment of rabbits with garlic (800 mg/kg) and/or selenium (1 mg/kg body weight) by 2 h. The present study showed that motilities, semen volumes, morphologies, sperm counts, testosterone, and estrogen levels were significantly decreased after 4, 8, and 12 weeks of tramadol treatment. In addition, the protein expressions of CYP 21A2, CYP 19, and 11A1 were down-regulated in the testes of the tramadol-treated rabbits. On the other hand, pretreatment of rabbits with garlic, selenium, and/or garlic-selenium for 2 h before administration of tramadol restored the downregulated CYP 21A2 and 11A1 to their normal levels after 12 weeks of tramadol treatment. Activities of antioxidant enzymes including glutathione reductase, glutathione peroxidase, glutathione S-transferase, catalase, superoxide dismutase, and levels of glutathione were inhibited in the testes of tramadol-treated rabbits. On the other hand, free radical levels were significantly increased in the testes of tramadol-treated rabbits for 12 weeks. Interestingly, such changes in the activities of antioxidant enzymes as well as free radical levels caused by tramadol were restored to their normal levels in the rabbits pretreated with either selenium, garlic, and/or their combination. Histopathological investigations showed that tramadol caused substantial vacuolization with the presence of damaged immature spermatozoid in the testes. However, selenium and garlic treatments showed an increase in healthy sperm production with normal mitotic and meiotic divisions. The present study illustrated for the first time the mechanisms of low steroid hormone levels in the testes of tramadol-treated rabbits which could be due to the downregulation of CYPs proteins, induction of oxidative stress, and inhibition of antioxidant enzyme activities. In addition, the present data showed that such toxic effects of tramadol were attenuated and restored to their normal levels after pretreatment of rabbits with garlic, selenium, and/or their combination. This finding may pave the way for a new approach to reducing the toxicity of tramadol.

Pomegranate Seeds Extract Possesses a Protective Effect against Tramadol-Induced Testicular Toxicity in Experimental Rats.

Tramadol is a centrally acting opioid analgesic that is extensively used. The chronic exposure to tramadol induces oxidative stress and toxicity especially for patients consuming it several times a day. Previously, we and others reported that tramadol induces testicular damage in rats. This study was conducted to investigate the possible protective effect of pomegranate seed extract (PgSE) against tramadol-induced testicular damage in adult and adolescent rats. Male rats were orally treated with tramadol or in a combination with PgSE for three weeks. Testes were then dissected and analyzed. Histological and ultrastructural examinations indicated that tramadol induced many structural changes in the testes of adult and adolescent rats including hemorrhage of blood vessels, intercellular spaces, interstitial vacuoles, exfoliation of germ cells in lumen, cell apoptosis, chromatin degeneration of elongated spermatids, and malformation of sperm axonemes. Interestingly, these abnormalities were not observed in tramadol/PgSE cotreated rats. The morphometric analysis revealed that tramadol disrupted collagen metabolism by elevating testicular levels of collagen fibers but that was protected in tramadol/PgSE cotreatment at both ages. In addition, DNA ploidy revealed that S phase of the cell cycle was diminished when adult and adolescent rats were treated with tramadol. However, the S phase had a normal cell population in the cotreated adult rats, but adolescent rats had a lower population than controls. Furthermore, the phytochemistry of PgSE revealed a high content of total polyphenols and total flavonoids within this extract; besides, the DPPH free radical scavenging activity was high. In conclusion, this study indicated that PgSE has a prophylactic effect against tramadol-induced testicular damage in both adult and adolescent ages, although the tramadol toxicity was higher in adolescent age to be completely protected. This prophylactic effect might be due to the high antioxidant compounds within the pomegranate seeds.

Comparison of efficacy of diclofenac and tramadol in relieving pain in patients of acute pancreatitis: A randomized parallel group double blind active controlled pilot study.

BACKGROUND: Opioids and non steroidal anti inflammatory drugs (NSAIDs) are commonly used for pain relief in acute pancreatitis (AP). Opioids carry risk of sphincter of oddi constriction. Although diclofenac prevents post endoscopic retrograde cholangio-pancreatography (ERCP) pancreatitis, few reports of diclofenac associated AP are also present. Although, both tramadol and diclofenac are commonly used for pain relief in AP, no study has evaluated their comparative efficacy and safety. MATERIALS AND METHODS: Forty-six eligible participants were randomized to either diclofenac or tramadol. Primary objectives of our study were improvement in pain intensity on visual analogue scale (VAS pain score after 1 hr of drug administration) and number of patients requiring supplementary analgesia. The secondary objectives were total number of times of supplementary analgesia requirement, time to significant decrease (33%) in VAS pain score from baseline, number of painful days (VAS pain score >5), VAS pain score on 7th day, side effects, all cause death and complications of pancreatitis between the two groups. RESULTS: Although 46 patients were randomized, the final analysis included 41 participants. Five patients were withdrawn from the study (intubation = 3, altered sensorium = 2). No significant difference was seen in terms of VAS score after 1 hr of drug administration, number of patients requiring supplementary analgesic and number of painful days. However, time taken to significant reduction of pain was lower in the diclofenac group (p = .028). Both the agents were comparable in terms of safety. Although complications were less in the diclofenac group, the difference was not statistically significant. CONCLUSION: Both diclofenac and tramadol are equally effective in controlling pain in AP with similar safety profile. SIGNIFICANCE: There are no studies that have compared the safety and efficacy of two commonly used analgesics for pain relief in patients with AP. We found that both diclofenac and tramadol are equally effective in decreasing the pain associated with AP. There is also no significant difference in the incidence of side effects between both the groups. Hence both diclofenac and tramadol can be used safely and effectively for pain control in AP. TRIAL REGISTRATION: The trial was registered with clinical trials registry India (Number- CTRI/2018/05/014309).

Fixed time interval compared with on-demand oral analgesia protocols for post-caesarean pain: a randomised controlled trial.

OBJECTIVES: To compare the efficacy, safety and satisfaction from two modes of oral analgesia administration for the treatment of post-caesarean pain in the first 48 h following surgery: on-demand versus fixed time interval administration. DESIGN: Open label parallel-group, randomised-controlled trial from February to December 2013. SETTING: University-affiliated hospital in Israel. POPULATION: Two-hundred women who underwent caesarean delivery with regional anaesthesia. METHODS: Patients were randomly assigned to receive predetermined combinations of tramadol, paracetamol and diclofenac either following patient demand or at predetermined 6-h intervals for the first 48 h. If the patient requested additional analgesia, Percocet (oxycodone and paracetamol) was given as a rescue treatment. MAIN OUTCOME MEASURES: Pain intensity and satisfaction were self-evaluated with visual analogue scale of 0 (no pain/least satisfaction) to 10 (worst pain/highest satisfaction). Breastfeeding, need for supplemental formula, and maternal and neonatal adverse effects were also evaluated. RESULTS: The 'fixed time interval' group, compared with the 'on-demand' group, had lower mean pain score (2.8 ± 0.84 versus 4.1 ± 0.48, respectively; P < 0.0001), higher satisfaction rate (9.1 ± 1.2 versus 8.3 ± 1.5, respectively; P < 0.0001), more breastfeeds (23.7 ± 6.5 versus 19.2 ± 6.2, respectively; P < 0.0001) and less use of supplemental formulas (8.2 ± 5.2 versus 11.9 ± 6.5, respectively; P < 0.0001). The number of times that drugs were given was slightly higher in the 'fixed time interval' group without an increase in maternal adverse effects, which were mild. No adverse effects were reported for the neonates. CONCLUSION: Administration of oral analgesia in fixed time intervals is superior to drug administration following patient demand without increasing maternal or neonatal adverse outcomes. TWEETABLE ABSTRACT: Oral analgesia in fixed time intervals is superior to analgesia following demand.

Pharmacologic treatment of hand-, knee- and hip-osteoarthritis.

Osteoarthritis (OA) is a joint disease of high prevalence and affects > 90 % of the population, depending on several risk factors. Symptomatic OA is less frequent, but requires an individually tailored therapeutic regimen consisting of non-pharmacological and pharmacological treatment modalities. Pharmacologic therapy, however, is mainly limited to analgetic and anti-inflammatory agents; structure modifying remedies do not exist. The therapeutic approach to hand-, knee- and hip-OA is basically similar and differs only at some minor points. Generally, topical agents or paracetamol are recommended as first-line agents. If unsuccessful oral non-steroidal anti-inflammatory drugs (NSAIDs) or COX-2-selctive inhibitors should be introduced. Tramadol is an option in the case patients will not respond satisfactorily to NSAIDs. Glucosamine and chondroitine sulphate are no longer recommended in knee and hip OA, but chondroitine might be efficient in treating hand OA. Oral NSAIDs should be prescribed with caution due to potential side effects. Opioids are not recommended as their benefits are outweighed by an increased risk for serious adverse events.

Tramadol and levobupivacaine wound infiltration at cesarean delivery for postoperative analgesia.

PURPOSE: The aim of the present study was to investigate whether levobupivacaine and tramadol wound infiltration decreases postoperative pain following Cesarean section and reduces the need for analgesics in the immediate post-delivery period. METHODS: Ninety patients (aged 18-40 years) scheduled for elective Cesarean section under general anesthesia were randomly allocated to one of the three groups: the placebo group (group P) received 20 mL local wound infiltration with 0.9 % saline solution; the levobupivacaine group (group L) received 20 mL local wound infiltration with levobupivacaine 0.25 %; and the tramadol group (group T) received 20 mL local wound infiltration with 1.5 mg/kg tramadol within 0.9 % saline solution. Following the closure of the uterine incision and the rectus fascia, 20 mL solution was infiltrated subcutaneously along the skin wound edges. The primary outcome was 24-h tramadol consumption. Secondary outcomes were recorded VAS scores, diclofenac requirement, fever, vomiting, and wound infection. RESULTS: At 15 min postoperatively, VAS values were lower in groups T and L than group P (P = 0.0001). The mean 24-h tramadol consumption was lowest in group T (P = 0.0001) and it was lower in the group L compared to group P (P = 0.007) (401.6, 483.3, and 557.5 mg for T, L, and P groups, respectively). There was no difference among groups regarding the need for supplemental analgesia (rescue diclofenac doses) (P > 0.05). CONCLUSIONS: We conclude that wound infiltration with tramadol and levobupivacaine in patients having Cesarean section under general anesthesia may be a good choice for postoperative analgesia.

Significance of the biopharmaceutical properties of tramadol sustained-release formulations for chrono-pharmacologically optimized treatment of pain from various sources.

UNLABELLED: Tramadol is currently one of the most frequently used opioid analgesics in the world. OBJECTIVE: The objective of this study was to investigate the rate and extent of tramadol bioavailability following evening versus morning intake of an extended-release pellet system designed for once daily administration. Moreover, the suitability of the preparation for chrono-adjusted pharmacotherapy was to be investigated. METHODS: 18 male and female volunteers were enrolled in the study and treated with 200 mg tramadol extended-release capsules, which were to be taken in the fasted state between 7:30 and 8:00 a.m. or p.m., respectively. The parent compound and its O-desmethyl-metabolite were analyzed in plasma samples using a LC-MS/MS procedure. RESULTS: Maximum exposure of tramadol (geometric means of C(max)-values) was determined as 289.3 ng/ml after morning and 283.1 ng/ml after evening administration. Extent of tramadol exposure (geometric means of AUC(0-48)-values) was calculated as 4,802.5 ng x h/ml after morning and 4,767.0 ng x h/ml after evening administration. Also tmax-values were comparable after morning and evening administration (9.00 vs. 9.50 hours). Statistical analyses, based on conventional bioequivalence approach, revealed no evidence of any impact of the time-point of administration on the biopharmaceutical performance of the dosage form investigated here. CONCLUSIONS: Bioavailability of the extended-release tramadol capsules for once daily administration is not affected by the time-point of administration. Total and maximum exposure of the product was bioequivalent after intake in the morning and at night. Thus, the time-point of administration may be adjusted to the patient's needs without any significant change in the in-vivo performance.

Effect of transcutaneous electrical acupoint stimulation on nausea and vomiting induced by patient controlled intravenous analgesia with tramadol.

OBJECTIVE: To observe the effect of transcutaneous electrical acupoint stimulation (TEAS) on nausea and vomiting (N&V) induced by patient controlled intravenous analgesia (PCIA) with Tramadol. METHODS: Sixty patients who were ready to receive scheduled operation for tumor in the head-neck region and post-operation PCIA, aged 39-65 years, with the physique grades I-II of ASA, were randomized into two groups, A and B, 30 in each group. The pre-operation medication, induction of analgesia and continuous anesthesia used in the two groups were the same. TEAS on bilateral Hegu (LI4) and Neiguan (PC6) points was intermittently applied to the patients in group A starting from 30 min before analgesia induction to 24 h after operation, and the incidence and score of nausea and vomiting, antiemetic used, visual analogue scores (VAS), and PCIA pressing times in 4 time segments (0-4, 4-8, 8-12 and 12-24 h after the operation was finished) were determined. The same management was applied to patients in Group B, with sham TEAS for control. RESULTS: The incidence and degree of N&V, as well as the number of patients who needed remedial antiemetic in Group A were less than those in Group B. The VAS score and PCIA pressing time were lower in Group A than those in Group B in the corresponding time segments respectively. CONCLUSION: TEAS could prevent N&V induced by PCIA with Tramadol.

Co-administration of rofecoxib and tramadol results in additive or sub-additive interaction during arthritic nociception in rat.

Over the decades, nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids are the most commonly used analgesics in the management of acute and chronic pain. In order to assess a possible antinociceptive interactions, the antinociceptive effects of rofecoxib p.o., a preferential inhibitor of cyclooxygenase-2, and tramadol-hydrochloride p.o., an atypical opioid analgesic, administered either separately or in combination, were determined using a rat model of arthritic pain. The data were interpreted using the surface of synergistic interaction (SSI) analysis and an isobolographic analysis to establish the nature of the interaction. The SSI was calculated from the total antinociceptive effect produced by the combination after subtraction of the antinociceptive effect produced by each individual drug. Female rats received orally rofecoxib alone (1.0, 1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg), tramadol alone (1.8, 3.2, 5.6, 10.0, 17.8, 31.6 and 56.2 mg/kg) or 12 different combinations of rofecoxib plus tramadol. Five combinations exhibited various degrees of sub-additive (i.e. less than the sum of the effects produced by the each drug alone) antinociceptive effects (3.2 mg/kg tramadol with 7.8 mg/kg rofecoxib; 5.6 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib; 10.0 mg/kg tramadol with either 10.0 or 17.8 mg/kg rofecoxib), whereas the other 7 combinations showed additive antinociceptive effects (i.e. the sum of the effects produced by each agent alone). Three combination of rofecoxib+tramadol (10.0+5.6, 10.0+10.0, and 17.8+5.6 mg/kg respectively) presented high sub-additive interactions (P<0.002: Q=9.5). The combination rofecoxib (17.8 mg/kg)+tramadol (10.0 mg/kg) caused gastric injuries less severe than those observed with indomethacin, but more severe than those obtained with rofecoxib or tramadol in single administration. The antinociceptive interaction of rofecoxib and tramadol suggests that combinations with these drugs may have no clinical utility in pain therapy.

Inpatient initiation of buprenorphine maintenance vs. detoxification: can retention of opioid-dependent patients in outpatient counseling be improved?

Buprenorphine-naloxone is an office-based opioid agonist released in 2003 in the United States for the maintenance of heroin- and other opioid-dependent patients. Concern has been raised that the medication will distract or otherwise inhibit patients from participating in a holistic recovery program or abstinence-based counseling. Using a retrospective chart review, the first thirty opioid-dependent patients induced on buprenorphine maintenance therapy in an inpatient detoxification unit were compared to thirty age- and gender-matched patients who underwent detoxification (with a tramadol taper) and referral to intensive outpatient treatment. The clinical outcomes were a comparison of completion rates for an intensive outpatient program (IOP) and retention in treatment after twelve weeks of aftercare therapy. Patients induced on buprenorphine maintenance over three days had similar relief of withdrawal symptoms to patients detoxified from opioids over five days with tramadol. Patients maintained on buprenorphine had a markedly increased initiation of IOP and remained in outpatient treatment longer than patients who were detoxified (8.5 wks vs. 0.4 wks, p < 0.001). This study indicates that induction and maintenance on buprenorphine may be more effective than detoxification for engaging and retaining patients in abstinence-based comprehensive outpatient addiction treatment.

[Tramadol hydrochloride in the treatment of postoperative shivering]. / Tramadol gidrokhlorid dlia lecheniia posleoperatsionnoi drozhi.

A double blind study of the therapeutic effect of the opioid tramadol hydrochloride (Gruenenthal, Germany) in the treatment of postoperative trembling was undertaken in 2 groups of patients (50 patients in each) versus that of placebo. The results obtained denoted that tramadol at 1-2 mg/kg arrested completely the postoperative trembling or cut significantly its intensity in 49 (98%) patients. Such high efficiency of tramadol as compared to that of other opioids can be explained by its dual mechanism of action. The dependence of an effective tramadol dose on intensity of shivering and on degree of impaired temperature hemostasis was demonstrated. A comparison of hemodynamic parameters observed before and after the administration of tramadol did not reveal any valuable changes in arterial pressure or cardiac beat rate. Mildly intensified sedation was registered in 17 patients, which is typical of all opioids.

Patient-controlled analgesia with tramadol versus tramadol plus lysine acetyl salicylate.

UNLABELLED: By using a patient-controlled analgesia (PCA) delivery system, we compared the clinical advantages and disadvantages of PCA with tramadol and PCA with a mixture of tramadol plus lysine acetyl salicylate (a soluble aspirin). Fifty adult patients who had undergone major orthopedic surgeries were enrolled into a prospective, randomized, and double-blinded study. The general anesthesia was performed in a standard manner. At the beginning of wound closure, an equal volume dose of either tramadol 2.5 mg/kg (Group 1) or tramadol 1.25 mg/kg + lysine acetyl salicylate 12.5 mg/kg mixture (Group 2) was administered slowly IV. These solutions were continued postoperatively for IV PCA. Pain control, patient satisfaction, vital signs, and adverse effects were assessed for 48 h. Visual Analog Scale

The effect of tramadol on dento-alveolar surgical pain.

The aim of the study was to assess the analgesic effect of tramadol in the relief of pain after dentoalveolar operations that involve the removal of bone and suturing. Four-hundred and fifty-two patients over the age of 18 years who were to undergo removal of impacted teeth (n = 362), removal of root (n = 79), or alveolectomy, enucleation of cysts, or removal of soft tissue (n = 11) under local anesthesia were studied. Patients were randomly allocated to receive tramadol 100 mg or 50 mg four times daily, or 50 mg twice daily, or placebo. Median pain scores on the day of operation in the three tramadol groups were similar (2 in each group, ranges 1-5, 1-4.8, and 1-5 respectively) and were all significantly lower than that in the placebo group (2.3 range 1-4.2). The median number of Paracetamol tablets taken by patients in the three tramadol groups was 2 (ranges 0-8, 0-12 and 0-8 respectively), and were all significantly less than in the placebo group (4, range 0-12). More patients given tramadol reported complete pain relief than the placebo group. The advantages of tramadol continued over the next 2 days. There were no serious or unexpected adverse effects. It is concluded that tramadol is an effective analgesic after dentoalveolar operations.

Dose dependent time course of the analgesic effect of a sustained-release preparation of tramadol on experimental phasic and tonic pain.

1. The aim of this study was to investigate the analgesic effect and its duration of a new sustained-release preparation of tramadol in an experimental pain model based on pain-related chemosomatosensory evoked potentials (CSSEPs) and subjective intensity estimates of painful phasic and tonic stimuli. 2. Twenty volunteers participated in a randomised, double-blind, three-fold cross-over study. Measurements were obtained before and 0.5, 1, 4, 6, and 12 h after administration of the drug (100 mg, 200 mg and placebo orally). CSSEPs were recorded after stimulation of one nostril with phasic, painful CO2 pulses. The other nostril was stimulated with a constant stream of dry air, which produced a tonic painful sensation. Subjects rated the perceived intensity of phasic and tonic stimuli via visual analogue scales. In order to test for nonspecific effects, acoustic evoked potentials (AEPs) were recorded, the spontaneous EEG was analysed in the frequency domain, the subject's vigilance was assessed in a tracking task, and the side effects of the drug were monitored. 3. The sustained-release preparation of tramadol produced a significant dose-related decrease in CSSEP amplitudes when compared with placebo. The reduction in amplitudes outlasted the observation period of 12 h, demonstrating the prolonged duration of the analgesic effect. 4. A dose-related significant decrease could be observed for the estimates of tonic pain. Similar to the decrease of amplitudes of the CSSEP, the reduction of the ratings of tonic pain outlasted the observation period of 12 h. The observed slight decrease in the estimates of phasic pain under medication did not reach a statistically significant level when compared with placebo. No significant effect could be demonstrated for the perception of the phasic and the tonic pain as determined by the McGill-Questionnaire. 5. A significant dose-related increase in the estimates of the side effects 'drowsiness', 'vertigo' and 'sickness' but not for 'tiredness' could be demonstrated.