substance withdrawal syndrome

Drug addiction constitutes a global issue associated with severe personal, economic, social, and health problems. Saffron, an herbal medicine, has demonstrated potential therapeutic applications for mental and physical symptoms. This review assesses the efficacy of saffron crocin in managing the clinical and psychological complications of opioid substance withdrawal syndrome(OWS).

The research methodology entailed a comprehensive literature review spanning from 2010 to 2023, utilizing databases such as Scopus, PubMed, Embase, and Web of Science. The search focused on the impact of saffron crocin on clinical and psychological complications of opioid substance withdrawal syndrome. Human randomized controlled trials (RCTs) and animal studies published in English were included for data synthesis. Subsequently, information was collated based on the following parameters: study author, number of studies, dosage, control group, duration, outcome criteria, and primary outcomes.

Eight articles were analyzed, demonstrating the efficacy of saffron and crocin in treating opioid withdrawal syndrome (OWS) by ameliorating withdrawal symptoms and improving laboratory indicators.

While several RCTs support the effectiveness of saffron crocin in alleviating opioid withdrawal symptoms, further rigorous studies are warranted to corroborate these findings.

Opioids can lead to mood disorders, anxiety, depression, and cognitive impairment. Valproic acid (VPA) has neuroprotective effects that can prevent neural degeneration. This study aims to examine the impact of VPA on learning, social interaction, and depression in mice dependent on morphine.

Subjects were divided into four groups and received injections of saline, VPA, morphine, or a combination of VPA and morphine for eight days. Behavioral tests were conducted on day 8, and then administration of VPA and morphine was stopped, leading to spontaneous withdrawal syndrome. Behavioral tests were repeated on day 11, and histological analysis was performed on the hippocampus.

The preference index (PI%) decreased in the novel object recognition test in the VPA and morphine sulfate (MOR) groups compared to the control (CTL) group in the chronic phase. The concomitant administration of VPA and morphine caused an increase in social interaction criteria in both the chronic and withdrawal phases. The decrease in immobility time in the VPA and MOR + VPA groups compared to the CTL group in the withdrawal phase was not statistically significant in the tail suspension test (TST). In Nissl staining, the combination of MOR + VPA led to a significant decrease in the DC/All cell ratio compared to the individual MOR and VPA groups (P < 0.05).

VPA may improve social relationships and depression indices during morphine withdrawal. VPA may potentially mitigate the cellular changes in the CA1 of the hippocampus induced by morphine.

Promising results were obtained by using medicinal plants for the treatment and prevention of opioid withdrawal syndrome. A native Iranian plant, Echinophora platyloba, has shown analgesic effects that may be mediated through opioid receptors. Thus, the present research evaluated the effects of the ethanolic extract of E. platyloba on the acquisition of morphine dependence in mice.

Thirty-two male mice were randomly allocated into four groups of eight. Morphine dependence was induced in the mice by subcutaneous administration of morphine (50, 50, and 75 mg/kg)×3 days, plus a single dose of morphine (50 mg/kg) on the fourth day. Withdrawal syndrome was precipitated by intraperitoneal injection of naloxone (4 mg/kg) 2 hours after the last dose of morphine. On days of dependence induction and before each morphine dose, the mice received intraperitoneal injections of saline (10 ml/kg) or plant extract (25, 50, and 75 mg/kg). After the injection of naloxone, the symptoms of withdrawal syndrome in each animal were monitored for 30 minutes.

Administering morphine with this method induced morphine dependence in mice that were treated with saline before morphine. However, the mice that received the plant extract showed a significant decrease in the withdrawal symptoms including the number of jumping (P<0.01), rearing (P<0.05), grooming (P<0.05), and diarrhea (P<0.01) compared with the saline-treated mice.

Administration of the hydro-ethanolic extract of E. platyloba before morphine may inhibit the induction of morphine dependence. Therefore, the plant extract may be considered a therapeutic agent for the prevention of morphine dependence in morphine users.

The persistence of post-detoxification problems in drug addiction is one of the disadvantages of the ultra-rapid opioid detoxification (UROD) method. Transcranial direct current stimulation (tDCS) has been introduced in experimental addiction treatment for some years. Results of pilot studies suggest that it might be a promising method for addiction treatment. This study explores the adjunctive application of tDCS during treating opiate addiction with the UROD approach.

This double-blind, sham-controlled clinical trial was carried out on patients with substance abuse admitted to the Bahman Clinic of Yazd City in Iran (from March to September 2014). Forty participants were randomly allocated to treatment and control groups. Two sessions of tDCS (real or sham) over dorsolateral prefrontal cortices (DLPFC) were applied, accompanied by UROD. Withdrawal symptoms and craving were assessed by the drug desire questionnaire and objective opiate withdrawal scale before UROD and for the 24-hour interval after.

Transcranial direct current stimulation optimized the opiate addiction treatment through craving and withdrawal syndrome alleviation.

The study results indicate that prefrontal tDCS may promote the efficacy of the UROD method in opioid addiction.

GABAergic drugs have extensive interference with morphine’s pharmacological effects, including dependence. 

The present study was conducted to evaluate the effects of isoniazid, a GABAergic agent, on the acquisition and expression of morphine-induced dependence in male mice.

Sixty-four male mice were used. The mice became dependent on morphine by administrating ten doses of morphine in four days. For the precipitation of the morphine withdrawal signs (jumping, diarrhea, and weight loss), two hours after the last dose of morphine, the mice received naloxone (4 mg/kg, IP). In the expression experiment, four groups of mice received saline or isoniazid (25, 50, and 75 mg/kg, IP) one hour before naloxone. In the acquisition experiment, the other four groups, one hour before the first six doses of morphine, received saline or isoniazid (25, 50, and 75 mg/kg, IP). 

In the expression experiment, all doses of isoniazid decreased the number of jumping in mice, but only the lowest dose influenced diarrhea (increased weight of diarrheal stool) significantly. The higher doses of isoniazid (50 and 75 mg/kg, IP) caused a significant reduction in the percentage of weight loss, but its lowest dose (25 mg/kg, IP) significantly increased the sign. In the acquisition experiment, isoniazid (25, 50 mg/kg IP) decreased the number of jumping and the percentage of weight loss, but not the weight of diarrheal stool.

Isoniazid may be a good candidate to prevent morphine withdrawal signs.

The most effective treatment for withdrawal syndrome in Opioid-dependent patients admitted tointensive care units (ICUs) remains unknown. This study aimed to compare fentanyl and methadone in this re-gard.

This prospective, single-blinded, controlled pilot study was conducted on opioid-dependent in-tubated patients admitted to the toxicology ICU of Loghman Hakim Hospital, Tehran, Iran, between August 2019and August 2020. Patients were alternately assigned to either fentanyl or methadone group after the initiation oftheir withdrawal syndrome. Duration and alleviation of the withdrawal signs and symptoms, ICU and hospitalstay, development of complications, development of later signs/symptoms of withdrawal syndrome, and needfor further administration of sedatives to treat agitation were then compared between these two groups.

Median age of the patients was 42 [interquartile range (IQR): 26, 56]. The two groups were similar in terms ofthe patients’ age (p = 0.92), sex (p = 0.632), primary Simplified Acute Physiology Score (SAPS) II (p = 0.861), andClinical Opiate Withdrawal Score (COWS) before (p = 0.537) and 120 minutes after treatment (p = 0.136) witheither methadone or fentanyl. The duration of intubation (p = 0.120), and ICU stay (p = 0.572), were also similarbetween the two groups. The only factor that was significantly different between the two groups was the timeneeded for alleviation of the withdrawal signs and symptoms after the administration of the medication, whichwas significantly shorter in the methadone group (30 vs. 120 minutes, p = 0.007).

It seems thatmethadone treats the withdrawal signs and symptoms faster in dependent patients. However, these drugs aresimilarly powerful in controlling the withdrawal signs in these patients.

The aim of this double-blind clinical trial was to evaluate the efficacy and safety of haloperidol on acute opioid withdrawal symptoms.

In this randomized double-blind clinical trial, fifty-two eligible patients were assigned to two groups according to previous opioid consumption, low dose (LD) and high dose (HD). Then, patients in each group were randomly assigned to one of the two subgroups of haloperidol or placebo. Patients in the haloperidol subgroup in LD group received 2.5 mg and in HD group received 5 mg/day haloperidol with methadone. Methadone was discontinued ten days after the beginning of the study and haloperidol or placebo continued for up to two weeks after methadone discontinuation. The severity of opioid withdrawal symptoms was assessed with the Objective Opioid Withdrawal Scale (OOWS) every other day.

Although both treatment protocols either in LD or HD opioid consumption groups significantly increased the score of the OOWS over the trial period (all subgroups, P < 0.001), the combination of 2.5 mg/day of haloperidol and methadone in LD opioid consumption group showed a significant superiority over methadone alone in decreasing opium withdrawal symptoms during the study (P = 0.001). The frequency of adverse effects was comparable between two treatment protocols in both groups (P > 0.05).

The results of this study suggest that 2.5 mg/day of haloperidol may be an effective adjuvant agent in the management of opium withdrawal symptoms in patients with LD opioid consumption. Nevertheless, results of larger controlled trials are needed before recommendation for a broad clinical application can be made

Drug addiction triggers the infliction of a variety of diseases. Various subjects have indicated that during the withdrawal syndrome period, the immune system is weakened..
This study aimed to investigate the changes in serum levels of interferon-gamma (IFN-γ) and interleukin-17 (IL-17) during the morphine withdrawal syndrome induced by 8 weeks of moderate exercise and their effects on the immune system function..
Twenty-four male Wistar rats (220 ± 10 g) were divided into four groups (n = 6): healthy control (HC), addicted control (AC), healthy trained (HT), and addicted trained (AT) groups. AC and AT groups were made addicted to morphine sulfate (0.4 mg/mL) in 21 days. To ensure their dependence on morphine, naloxone (3 mg/kg, i.p.) was injected into the body of a number of the rats. HT and AT groups were made to run on a treadmill 5 days per week for 8 weeks while time and speed gradually increased. Both prior to the exercises and 24 hours after the last training session, blood samples were collected from all the animals, and serum IFN-γ and IL-17 serum levels were measured using the ELISA method. This research was performed at the Bu-Ali Sina University, Hamadan, Iran..
After 8 weeks of exercise, a significant increase was observed in the serum IFN-γ level in the HT group (251.17 ± 13.045) in comparison with the HC group (234 ± 12.884) (P = 0.045). Furthermore, the serum IFN-γ level in the AT group (218.33 ± 5.164) in comparison to the AC group (190.67 ± 8.477) showed a significant increase (P = 0.000). In addition, the serum level of IFN-γ in the HT group showed a significant increase compared to the AT group (P = 0.000). After 8 weeks of exercise, there was a significant decrease in the serum IL-17 level in the HT group (22.67 ± 4.46) compared with the HC group (38.17 ± 7.68) (P = 0.005). In addition, a significant decrease was observed in serum IL-17 in the AT group (42.17 ± 7.41) in comparison with the AC group (57.17 ± 7.83) (P = 0.007). In addition, the serum IL-17 level in the HT group significantly decreased in comparison with the AT group (P = 0.001)..
Moderate exercise for 8 weeks increased the IFN-γ and decreased the IL-17 serum levels in the morphine-dependent rats. For this reason, this type of exercise can improve the function of the immune system during morphine withdrawal syndrome..

Individuals, during opioid withdrawal period, experience symptoms such as dysphoria, insomnia, anxiety, irritability, nausea, agitation, tachycardia, and hypertension which may trigger drug seeking behavior and relapse. This study was conducted with the aim of determining the effect of Tranquival tablets on some heroin withdrawal symptoms in addicted patients referred to an outpatient clinic.
In this single-blind quasi-experimental study, 69 patients (37 patients in intervention group and 32 in control group) suffering from heroin withdrawal syndrome were allocated randomly to study groups. In the intervention group, 1 Tranquival tablet was administered 1 hour before sleeping each night for 6 weeks. In the control group, 1 tablet of clonazepam (1 mg) was administered at the same time. The Pittsburgh Sleep Quality Index (PSQI), Hamilton Anxiety Rating Scale (HAM-A), and visual analogue scale (VAS) were completed at the beginning, 3 weeks later, and the end of the study. Data were analyzed using Student’s t-test, repeated measures analysis, and chi-square test.
During the study period in both groups, withdrawal symptoms significantly decreased (P 0.050). Furthermore, the Bonferroni correction showed an relationship between Tranquival and clonazepam groups in terms of mean anxiety at the begining and the end stage of assessment (P = 0.012). However, these relationships were insignificant in terms of mean sleep and muscular pain (P = 0.153 and P = 0.267, respectively).
Tranquival was as effective as clonazepam in the reduction of muscular pain and anxiety, and improvement of sleep quality in patients suffering from heroin withdrawal syndrome.

During withdrawal, patients experience different symptoms. These symptoms are associated with relapse. Understanding different outcomes of methamphetamine abstinence is useful for finding better treatments for dependence.. This study aimed to show the effects of abstinence on depression, anxiety, and quality of life in methamphetamine users..Patients and A prospective quasi-experimental (before and after study) method was used to show the effect of 3 weeks abstinence on depression, anxiety, and quality of life. A convenient sample of addicted people entered into the study and 34 people completed the study. Beck Depression Scale, Cattell Anxiety Inventory and Short Form Health Survey (SF-36) (for assessing quality of life), were used for outcome assessments.. The mean depression score after abstinence decreased significantly (P < 0.001). Both hidden and obvious anxiety and total anxiety had a high level at admission and after 3 weeks of abstinence, the mean level of anxiety did not change significantly (P < 0.096). However, the quality of life increased after 3 weeks of abstinence (P < 0.001).. Depression and anxiety are prevalent in methamphetamine users. Short-term abstinence improves depression and quality of life but does not improve anxiety in methamphetamine abusers. During follow up of these patients, addressing depression and anxiety is important to achieve better results..

Alcohol use disorders (AUDs) are a health problem of high prevalence in most communities and such problems account for 5% of the total burden of disease worldwide. Clinical toxicologists are commonly required to treat patients having AUDs and associated drug/alcohol-related harm. There have been recent changes to some of the diagnostic criteria (notably in DSM V) relevant to AUDs, with older terms “alcohol abuse” and “alcohol dependence” no longer being classified. AUDs may sometimes not be clearly recognizable and use of evidence-based screening interventions can help identify such conditions and lead to effective brief interventions (e.g. SBIRT programs in emergency departments). AUDs are viewed as chronic disorders of alcohol consumption occurring across a spectrum of severity. While most AUDs are mild to moderate in severity and usually self-limiting conditions, more severe presentations are more commonly encountered by physicians in emergency settings. Hence, clinical toxicologists are more likely to see patients within the more severe form of disorder, at end of the spectrum of AUDs. Among this group of patients, multi-morbidity and particularly high mortality risk exists, and thus they usually require management collaboration with specialist services. Patients with AUDs are most likely to be recognized by a clinical toxicologist in the following scenarios: following acute heavy alcohol ingestion and subsequently developing acute alcohol intoxication (ethanol toxidrome), following accidental or intentional drug overdosage where alcohol has also been consumed, following acute alcohol consumption that has been associated with behavioral risk-taking and/or self-harming (e.g. poisoning, envenomation, etc.), when alcohol withdrawal reactions are severe requiring hospitalization and possibly following an adverse drug reaction.

Aloe vera is a medicinal herb used as an anti-inflammatory and sedative agent.. The current study aimed to evaluate the effect of Aloe vera aqueous extract on morphine withdrawal symptoms in morphine-dependent female rats..Patients and The current research was performed on 40 female Wista-Albino rats which were made dependent on morphine using Houshyar protocol and were randomly divided into five groups (A, B, C, D, and E). Group A did not receive any agent in the period of handling but other groups (B, C, D and E) received 5, 10, 20 and 40 mg/kg of Aloe vera aqueous extract by gavage, three times daily for a week, respectively. Withdrawal symptoms, stool form, agitation, disparity, floppy eyelids, and body mass variations were checked for 10 days. The obtained data were analyzed using SPSS v.11 software, and Friedman, Kruskal-Wallis, and Mann-Whitney statistical tests. Statistical difference was considered significant (P < 0.05).. The results of the present study showed that agitation, disparity, and floppy eyelids in group E were significantly higher than those of others groups; however, these symptoms in group C were significantly lower than those of the other groups.. The results of the present study revealed that the Aloe vera aqueous extract had various effects on morphine withdrawal syndrome in morphine-dependent female rats. .

Thymus species are well known medicinal plants which the previous studies suggested the involvement of the opioid system in them. This study aimed to investigate the effects of methanolic extract and essential oil of aerial parts of Thymus daenensis (TD), an endemic aromatic medicinal plant of Iran, on morphine withdrawal syndrome in mice. Experiments were performed in two groups of five, each group treated with extracts or essential oils of TD. Dependency was induced by subcutaneous injection of morphine for three consecutive days. On the fourth day, the last dose of morphine was injected two hours prior to intraperitoneal injection of naloxone while the extract or essential oil of TD was administered 30 minutes before naloxone. A period of 20 minutes after naloxone injection was considered the critical period of the withdrawal syndrome. The number of jumps, standing, leaning, and the weight of stools were recorded as withdrawal signs. The 200 mg/kg and 400 mg/kg doses of extract and all doses of essential oil decreased significantly the number of jumps, standing, leaning and the weight of stool. Administration of 100 mg/kg of extract only decreased the weight of stool and had no effect on the other factors. Extract and essential oil of TD attenuates morphine withdrawal behaviors in mice and may be useful in alleviating the signs and symptoms of opiate withdrawal syndrome in human.

Poisoning remains a major cause of hospital admission into the emergency department and intensive care unit. Proper diagnosis is the cornerstone for optimal management of poisoned patients. Since the definitive analytical confirmation of the nature of the toxicant involved in the poisoning cannot be rapidly obtained in the majority of healthcare facilities, diagnosis relies on the medical history and the rigorous clinical examination of the patients well as results of the routine biological tests and the electrocardiogram. Identification of the toxidromes addresses not only the correct diagnosis but also rules out other differential diagnoses. Despite no definitive predictive value, this clinical approach facilitates making decision on empirical treatments and emergent antidotes. Pharmacodynamic tests using specific antidotes including naloxone for opioids and flumazenil for benzodiazepines and its analogues are also helpful to assess the final diagnosis in comatose patients. The objective of this article is to review the toxidrome-based approach to common poisonings before toxicological analysis enables the confirmation of the initially suspected toxic etiology.

Zolpidem, a nonbenzodiazepine hypnotic, binds to the benzodiazepine binding site on the gamma-aminobutyric acid type A (GABA-A) receptors. Many studies have reported efficacy and safety of zolpidem in treatment of insomnia, low abuse, and dependence capability. However, many cases of zolpidem abuse and dependence were reported around the world. This case showed that zolpidem can exert abuse capability, euphoric mood, tolerance, and withdrawal syndrome.

Agitation is an early symptom of the acute opioid withdrawal syndrome in addicts that may start by inappropriate use of naltrexone. The current drug interventions are not efficient or need critical care as well. This study compares the clinical role of midazolam and diazepam for the management of agitation due to inappropriate use of naltrexone. In this double-blind randomized controlled clinical trial, 44 agitated addicts, who did not use any type of benzodiazepine, not on systematic central nervous system depressant drugs, without any known hypersensitivity to diazepam, midazolam, or any other component of their formulation and had no evidence for the need of critical care, were enrolled. An i.v. stat dose of 0.1 mg/kg diazepam and 0.1 mg/kg stat dose of midazolam and a 0.1 mg/kg/h infusion of these drugs were administered for different groups of patients, respectively. Agitation scores were recorded at 30, 60, 120 min after the start of drug administration using Richmond Agitation Sedation Scale score. A significant difference between the mean onset of agitation control in midazolam group (at 67 min) and diazepam group (at 81 min) was recorded. The difference of mean agitation score in the midazolam and diazepam group was only significant at 120 min. There was a negative correlation between agitation score and time elapsed from naltrexone administration to admission. Midazolam and diazepam may not be considered suitable and perfect pharmacologic agents for the initial controlling of agitation induced by naltrexone.