These secondary outcome data were used as an additional proxy measure to assess the availability of illegal drugs in specific regions, as has been carried out previously.All outcomes were systematically identified through publicly available illegal drug surveillance systems. Linear-by-linear association trend tests were carried out on annual estimates of all outcomes of interest. Price and purity estimates represent median values for each year, while estimates for seizures represent crude totals of quantity seized. All price estimates are expressed in 2011 USD and are, where possible, adjusted for purity.An online search of surveillance systems monitoring illegal drugs using two a priori defined inclusion criteria was carried out. Search terms included the following: drugs, illicit, illegal, price, purity, potency, surveillance system, government data, longitudinal, annual, estimate. Inclusion/exclusion criteria were as follows: only surveillance systems that included continuous longitudinal assessments of these outcomes of interest for at least 10 years were included because we specifically sought to assess the long-term impact of enforcement-based supply reduction strategies on illegal drug price and purity/ potency. Finally, data extraction was restricted to 1990 and onwards to focus on patterns of supply during recent decades. Data were obtained through online searches of registries of surveillance systems , governmental reports and peer-reviewed publications, through referrals from experts in the field, and through data requests to relevant organisations including the UNODC. All authors had complete access to all data and all had final responsibility to submit for publication. Ethics approval was not required given that we relied exclusively on publicly available data.We identified seven government surveillance systems that met inclusion criteria. Of these, 3 reported on international data, 3 on data from the USA and 1 on data from Australia.
One of the longest running surveillance system identified, the US-based Marijuana Potency Monitoring Project, is funded by the US National Institutes of Health and was established in 1975,cannabis cultivation technology while the most recent surveillance system was established in 2001 . With respect to international surveillance systems, the UNODC administers two separate surveillance systems that collect data from all participating UN member states: the Annual Reports Questionnaire surveillance system that collects price and purity/ potency data, and the Drug Seizures Database that collects seizure data. Finally, the European Monitoring Centre for Drugs and Drug Addiction administers the Reitox drug surveillance system network, which aggregates data from several country-level surveillance systems in Europe, as described below.24Table 1 presents surveillance systems that matched search criteria. An assessment of data provided by these surveillance systems demonstrated several broad trends. First, purity and/or potency of illegal drugs generally remained stable or increased overall during the study period. Second, the price of illegal drugs, with few exceptions, generally decreased. Third, seizures of cannabis, cocaine and opiates generally increased in major drug production regions and major domestic markets. Figure 1 presents data from the US Drug Enforcement Administration’s System To Retrieve Information from Drug Evidence . As can be seen, between 1990 and 2007 , the purity of heroin and cocaine, and the potency of cannabis herb in the US increased, while the inflation-adjusted and purity-adjusted retail street prices of these three drugs declined.25 Specifically, heroin purity increased by 60% , cocaine purity increased by 11% and cannabis herb potency increased by 161% during this time. During the same period, the prices of heroin, cocaine and cannabis decreased 81% , 80% and 86% , respectively.ICU patients frequently receive opioid and benzodiazepine medications to treat the pain, anxiety, and agitation experienced during a critical illness. Trauma ICU patients may require high and/or prolonged doses of opioids to manage pain associated with multiple open wounds, fractures, painful procedures, and/or surgery. They may also require benzodiazepines to prevent or manage anxiety and agitation and to facilitate effective mechanical ventilation . Although the effect of different pain and sedative medication regimens on TICU patients is unclear, prior evidence suggests that administration of opioid and benzodiazepine medications in the ICU setting is associated with the development of many complications including delirium and poor patient outcomes . Exposure to high or prolonged use of opioids and benzodiazepines may also contribute to both drug tolerance and drugphysical dependence .
Once drug dependence has developed, patients are then at risk for withdrawal syndrome , a group of serious physical and psychologic symptoms that occur upon the abrupt discontinuation of these medications . The effect of WS on patient recovery and prolonged ICU stay is unclear . Unlike in the PICU patient population, physical dependence during drug weaning of adult ICU patients exposed to prolonged doses of opioids and benzodiazepines has received little study. Indeed, there is a large discrepancy in the amount of literature regarding WS in the adult versus PICU populations. There are two descriptive studies with retrospective chart review designs and small samples in adult ICU surgical-trauma patients and burn ICU MV patients . Cammarano et al found that 32% of their sample developed WS after prolonged exposure to high doses of analgesics and sedatives. Brown et al found that all burn MV patients who received opioids and benzodiazepines for more than 7 days developed WS. In a prospective experimental study of major abdominal and cardiothoracic postsurgical ICU patients, 35% who received a combination of opioids and benzodiazepines developed marked withdrawal compared with 28% who received a combination of opioids and propofol . These three studies were reported more than 1 decade ago, prior to the current recommended change in sedative management . A recent prospective study of 54 TICU patients showed a lower occurrence of iatrogenic opioid WS than in previous studies . Regarding pediatric studies, two recent reviews evaluated 23 and 33 studies, respectively, of WS done in the PICU population . Of note, there is no valid and reliable WS assessment tool available for the adult ICU population, although there are two tools for pediatrics. These tools are the Withdrawal Assessment Tool-1 and the Sophia Observation withdrawal Symptoms-scale . The lack of a WS assessment tool for adult ICU patients may have contributed to the lower number of publications about WS in adults. This difficulty in the ability for clinicians to measure adult WS is particulary relevant considering the current U.S. opioid epidemic and was one of the reasons we undertook this exploratory work. Little is known about the actual occurrence of WS, risk factors, and its consequence in adult patients. Therefore, the objectives of this exploratory study were to identify risk factors associated with probable WS among adult TICU patients exposed to opioids and/or benzodiazepines; explore clinical characteristics, signs and symptoms, and outcomes among patients who developed probable WS, questionable WS, and patients who did not develop WS.Patients 21 years or older with an admission order to TICU at the Trauma Hospital of Puerto Rico and an expected exposure to opioids and/or benzodiazepines for 5 days or more were screened for study eligibility.
Patients who had head trauma with neurologic dysfunction, who were prisoners, and/or had alcohol use disorder by family or patient report were excluded . Consent was obtained in patients able to consent; for those unable to provide it, a family member provided authorization for the patient’s participation. When patients became capable of providing their own consent during the course of the study, they were asked about their desire to continue study participation and if the previously obtained data could be used.As established earlier, currently there is no validated tool for assessing WS in adult ICU patients which is a challenge in the study of WS in this population. Other challenges are that the signs and symptoms lack specificity, and there are similarities in these WS and signs and symptoms seen in other conditions like delirium, undersedation, pain, and anticholinergic toxidrome . This is particularly true for sign and symptoms related to CNS irritability and some nervous system activation . However, although not specific, WS has unique signs and symptoms related to gastrointestinal system dysfunction and some nervous system activation . Since we recognized the limitation of no validated assessment tool for adult ICU patients, we created a sign and symptom checklist to measure potential indicators of WS of opioids and/or benzodiazepines. For our checklist, we retrieved potential indicators from the Diagnostic and Statistical Manual of Mental Disorders , the International Classification of Diseases, 10th Edition Classification of Mental and Behavioral Disorders , and previous WS research in adult ICU patients to develop the checklist . Figure 2 depicts the signs and symptoms of opioid and/or benzodiazepine WS that were included on the checklist. Tachycardia and tachypnea were defined as more than 100 beats per minute and more than 30 breaths per minute, respectively, high blood pressure as a systolic pressure more than 150mm Hg, and/or diastolic pressure more than 90mm Hg. We used the Richmond Agitation-Sedation Scale score to determine level of arousal and the Confusion Assessment Method-ICU to determine delirium. The DSM-5 establishes that, to identify opioid and/or benzodiazepine withdrawal, the patient must develop three or more opioid and/or two or more benzodiazepine symptoms after cessation or a reduction in opioid or benzodiazepine doses after a prolonged use.Withdrawal signs and symptoms may begin to appear within 6–12 hours for short-acting opioids and 6–8 hours for benzodiazepine . Taking DSM-5 criteria into account and given that the checklist has not undergone a formal validation process,indoor grow cannabis we developed the following categories for our patients: “probable” WS: patients presenting with three or more sign/symptoms of opioid-WS and/or two or more sign/ symptoms of benzodiazepine-WS that were not present at baseline ; “no” WS: patients not presenting with the minimum sign/symptoms for opioid-WS and/or benzodiazepine-WS; and “questionable” WS: patients presenting with the required number of sign/symptoms, but one or more of these were present during baseline evaluation. For example, tachycardia that was present at baseline evaluation was not counted as a probable withdrawal sign during weaning.Recruitment and data collection were performed in TICU patients as well as patients with admission orders for TICU . If study patients were transferred to the intermediate unit while data collection was ongoing in the TICU, data collection continued in this unit. Baseline data were obtained from the patient’s clinical record or by family or patient interview. Daily and cumulative amounts of opioids and benzodiazepines and daily doses of other sedatives such as propofol and antipsychotics used from the arrival at Trauma Hospital and during the TICU stay were also collected.
Patient days on MV, length of TICU stay, and length of hospital stay were documented. Bedside patient assessment data using the sign and symptom checklist were collected on the fourth day of patients receiving opioids and/or benzodiazepines in order to establish baseline data. After the fourth day of receiving opioids and/or benzodiazepines, bedside patient assessment data were also collected once the start of the weaning process for up to 72 hours after the beginning of opioid and/or benzodiazepine weaning. If weaning was stopped and the patient returned to a similar previous dose, bedside measures ceased. When the weaning process was reestablished, measures began again and continued for up to 72 hours. Data on each of the signs and symptoms were collected twice a day .Due to a limited budget for this exploratory study, all data collection and assessments were performed by the first author.Patient demographic and clinical data are presented as medians for continuous variables and frequencies for categorical variables for patients as a total group and also according to WS category . To compare demographic and clinical characteristics in patients by WS category, we conducted Fisher exact test for categorical variables and Kruskal-Wallis test for continuous variables. A Bonferroni correction to adjust alpha for 13 comparisons was calculated, and a p value of less than 0.004 was necessary to determine statistical significance. A mixed-effects logistic regression was conducted to determine the contribution of demographic and clinical variables to the development of probable WS. We evaluated several candidate models for WS , in terms of their fit, using Akaike information criterion and Bayesian information criterion . AIC and BIC are the most commonly used criteria for candidate model selection in regression analysis, with lower values reflecting a better fit of the candidate model to the existing data .