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PubMed1998

Comparison of intrathecal morphine and continuous femoral 3-in-1 block for pain after major knee surgery under spinal anaesthesia.

Major knee surgery is associated with moderate or severe post-operative pain. Intrathecal morphine and continuous femoral 3-in-1 block were compared prospectively in 40 patients for pain after major knee surgery under spinal anaesthesia, with 4 mL isobaric 0.5% bupivacaine. In a random order, 20 patients received preservative free morphine 0.3 mg mixed with spinal bupivacaine. In 20 patients, following spinal anaesthesia with only bupivacaine, femoral 3-in-1 block was performed post-operatively with 0.5% bupivacaine 2 mg kg-1. The block was continued via a catheter with 0.25% bupivacaine 0.1 mL h-1 kg-1 until the next morning (24 h after induction of spinal anaesthesia). Intramuscular oxycodone was given as a rescue analgesic in all patients. Two patients from the femoral group were excluded due to technical failure. Three patients in the morphine group and one patient in the femoral group did not need any additional oxycodone. In the morphine group on average 2.8 (range 0-7) and in the femoral group 3.2 (0-5) additional doses of oxycodone were needed during the 24 h observation period. The mean pain scores were significantly lower in the morphine group at 9 and 12 h into the 24-h trial. Itching was seen only in the morphine group (40% of the patients). Other side effects were similar in the two groups. All patients were satisfied with their pain therapy. Both intrathecal morphine and femoral 3-in-1 block alone were insufficient for the treatment of severe pain after major knee surgery.

Aged↗

PubMed2002

Massive OxyContin ingestion refractory to naloxone therapy.

OxyContin (oxycodone hydrochloride controlled release) is a long-acting preparation of oxycodone that is used as an opioid analgesic to treat chronic pain conditions. We report a patient who ingested a massive quantity of OxyContin and had altered mental status, noncardiogenic pulmonary edema, and hypoventilation that proved refractory to naloxone administration. She required mechanical ventilation for 3 days before recovering completely. The severity and length of poisoning was likely related both to the quantity and formulation of the oxycodone ingested.

Female↗

PubMed1993

Effect of tropisetron, a 5-HT3 receptor antagonist, on analgesia and nausea after intrathecal morphine.

We have studied the effect of tropisetron, a 5-HT3-receptor antagonist, on postoperative nausea, vomiting and pain in 54 patients, aged 50-83 yr, after major hip or knee surgery. The patients were given subarachnoid injection of plain 0.5% bupivacaine, mixed with preservative-free morphine 0.3 mg, for surgical and postoperative analgesia. In a double-blind fashion, either tropisetron 5 mg (1 mg ml-1) or saline 5 ml was injected i.v. 30 min after spinal administration of bupivacaine and morphine. The number of patients needing i.m. oxycodone for pain relief, the total number of oxycodone doses or the mean time to the first i.m. oxycodone administration did not differ significantly between the two groups. The number of patients who became nauseated or vomited during the observation period did not differ significantly between groups. Seventeen patients had nausea and 11 vomited in the tropisetron group, compared with 20 and 13, respectively, in the control group during the first 24 h.

Aged↗

PubMed2000

An unusual multiple drug intoxication case involving citalopram.

A 47-year-old male with a history of drug abuse and suicide attempts was found dead at home. The death scene investigation showed evidence of cocaine abuse and multiple drug ingestion. Citralopram, a new selective serotonin reuptake inhibitor, cocaine, oxycodone, promethazine, propoxyphene, and norpropoxyphene were identified and quantitated in the postmortem samples by gas chromatography-mass spectrometry. The concentration of citalopram in the femoral blood was 0.88 mg/L. The heart blood concentration was 1.16 mg/L. Femoral blood concentrations of the other drugs were as follows: cocaine, 0.03 mg/L; oxycodone, 0.06 mg/L; promethazine, 0.02 mg/L; propoxyphene, 0.02 mg/L; and norpropoxyphene, 0.07 mg/L. Other tissue samples were also analyzed. The concentrations of cocaine, oxycodone, promethazine, and propoxyphene in the blood, liver, brain, and gastric contents did not suggest an intentional overdose. However, the possibility of multiple drug interactions including citalopram was evident. In this case, the citalopram concentrations were consistent with those reported in fatal cases involving multiple drug use. Citalopram was present in urine at a concentration of 0.9 mg/L.

Antidepressive Agents, Second-Generation↗

PubMed1989

Treatment of post-thoracotomy pain with intermittent instillations of intrapleural bupivacaine.

The effect of intrapleural bupivacaine in the treatment of post-thoracotomy pain was evaluated. Bupivacaine, 0.5% 20 ml, with adrenaline (5 micrograms/ml) was given through an indwelling intrapleural catheter, at 4-h intervals four times daily for 2 days. No pleural suction was applied during and 10 min after each injection. A control group received intramuscular oxycodone on request. A visual analogue scale (VAS), a pain questionnaire (PQ) and registration of the need for supplementary analgesics were used for the assessment of postoperative analgesia. Blood-gas analyses showed elevated PaCO2 values in both groups on the day of operation and on the first postoperative day, without differences between the groups. Plasma concentrations of bupivacaine did not reach toxic values, and no symptoms of central nervous toxicity or any other untoward reactions were found during the study period. Clinically, there was some pain relief after the intrapleural bupivacaine. The VAS and PQ scores 30 min after bupivacaine instillations diminished to an extent similar to that after oxycodone treatment. The need for analgesics during the day of operation was less in the bupivacaine group than in the control group (P less than 0.001). The number of oxycodone supplementation doses during 48 h postoperatively was, however, not smaller in the bupivacaine group than in the control group.

Bupivacaine↗

PubMed1995

Comparison of parenteral diclofenac and ketoprofen for postoperative pain relief after maxillofacial surgery.

Non-steroidal anti-inflammatory drugs (NSAID) effectively reduce the need for opioid analgesia after various types of surgery. The efficacy of diclofenac and ketoprofen to relieve pain after maxillofacial surgery was compared in the present study. In a randomized and double-blind fashion, 90 ASA I-II patients (16-60 yrs) were studied, divided into three groups: Thirty patients received 1.0 mg.kg-1 diclofenac i.v. after general anaesthesia induction, before surgical incision, and four hours later the same dose was given i.m. Thirty patients received ketoprofen 1.35 mg.kg-1 i.v. and i.m., as above, and a third group of 30 patients received a comparable volume of saline i.v. and i.m. The patients received supplemental analgesia using a patient controlled analgesia apparatus; the rescue medication consisted of 0.03 mg.kg-1 oxycodone i.v. (four-hour maximum dose was 0.4 mg.kg-1) during the 24-hour follow-up. The three groups were comparable regarding the type of maxillofacial surgery (osteotomies vs. soft tissue surgery). Overall, there was a lower need for i.v. oxycodone during the 24-hour period in the diclofenac group (269 doses) than in the ketoprofen group and in the saline group (388 doses, each) (P < 0.01). The significantly lower number of oxycodone administrations in the diclofenac group was a result of a distinguishable difference, particularly during the first four hours after surgery. There was no statistically significant difference in the incidence of side effects of the analgesic therapy between the three groups.

Adolescent↗

PubMed1997

Pharmacokinetics and pharmacodynamics of controlled-release opioids.

While pharmacokinetic/pharmacodynamic relationships for opioids have not been consistently demonstrable or sufficiently predictive, there remain compelling reasons to pursue such relationships. Among the reasons for pursuing pharmacokinetic/ pharmacodynamic relationships is the prospect of predicting the time-action characteristics of new therapeutics on the basis of early studies in normals using pharmacodynamic surrogates for analgesia. The realization of such a model could improve the efficiency of development of analgesics. Four studies involving 98 normals were conducted to determine whether significant and reproducible relationships existed for oxycodone in the form of an oral controlled-release tablet. All studies were analytically blinded and utilized a validated gas chromatographic/mass spectrometric, sensitive (0.2 ng/ml), and specific method for oxycodone (four studies) and oxymorphone (two studies) quantitation in 17 to 20 serial plasma samples over 36 to 48 hours following a single 20 mg (or 40 mg) dose in each study. Concurrent assessments included vital signs and opioid effect VAS questionnaires. The studies demonstrated significant relationships between plasma oxycodone (but not oxymorphone) and pharmacodynamic surrogates (particularly VAS "drug effect") and were predictive of the 12-hour duration of pain control and prompt onset of analgesia subsequently demonstrated in multiple clinical studies involving patients with various pathological pain syndromes. The results suggest that investigators can make earlier, accurate predictions of opioid analgesic pharmacodynamics in patients based on pharmacokinetic/pharmacodynamic studies in normal volunteers.

Administration, Oral↗

PubMed2004

Nociceptive sensitivity and opioid antinociception and antihyperalgesia in Freund's adjuvant-induced arthritic male and female rats.

The present study was designed to examine sex differences in complete Freund's adjuvant (CFA)-induced mechanical hyperalgesia and sex differences in opioid antinociception and anti-hyperalgesia. Female rats developed inflammation and hyperalgesia faster and exhibited greater peak hyperalgesia than male rats. In arthritic (CFA-treated) rats, lower thresholds were observed during estrus and proestrus, and in nonarthritic (vehicle-treated) rats, lower thresholds were observed during proestrus. Morphine and oxycodone were more potent in male than female arthritic rats, and butorphanol was more potent and effective in male than female arthritic rats. The potency of morphine was increased in arthritic rats, although to a greater magnitude in males. The potency of oxycodone was increased in male but not female arthritic rats. The potency of butorphanol was increased in arthritic male rats and the maximal antinociceptive effect of butorphanol was increased in arthritic female rats, but it did not result in greater than 20% antinociception. Morphine, oxycodone, and butorphanol all produced antihyperalgesic effects (returning thresholds of arthritic rats to the thresholds of nonarthritic rats) with greater potency in males than females. The peripherally acting opioid agonist loperamide produced intermediate levels of antinociception in male and female arthritic rats and no antinociception in nonarthritic rats. Loperamide was more potent in male than female arthritic rats at producing antihyperalgesia. These data demonstrate sex differences in arthritis-induced hyperalgesia and responsiveness to opioid analgesics. In arthritic rats, the antinociceptive effects of opioid agonists are most probably mediated by both central and peripheral opioid receptors, whereas their antihyperalgesic effects are mediated primarily by actions at peripheral opioid receptors.

Analgesics, Opioid↗

PubMed2004

The efficacy and safety of oral immediate-release oxymorphone for postsurgical pain.

In this double-blind, parallel-group study, we compared 3 oxymorphone immediate-release (IR) doses with placebo for efficacy and with oxycodone IR and placebo for safety in patients with acute moderate-to-severe postsurgical pain. During the single-dose phase (n = 300), patients received oxymorphone IR 10, 20, or 30 mg; oxycodone IR 10 mg; or placebo. All oxymorphone IR doses were superior for providing pain relief for 8 h (P < 0.05), with a significant analgesic dose response (P < 0.001). Significant pain intensity differences occurred by 45 min (20- and 30-mg doses; P < 0.05). Discontinuations for lack of efficacy totaled 42% among placebo-treated patients and 27% among those treated with oxymorphone IR. Patients requiring rescue medication after 3 h were allowed to receive additional study drug every 4 to 6 h as needed for the multiple-dose phase (n = 164). All oxymorphone groups maintained analgesia for 48 h. The median dosing interval was >9.5 h for oxymorphone IR 30 mg and > or =7 h for the other groups. Opioid-related adverse events, similar among groups, were generally mild or moderate. Oxymorphone IR 10, 20, or 30 mg provided significant dose-related pain relief compared with placebo, and this relief was maintained over several days with a safety profile comparable to that of oxycodone IR.

Adolescent↗

PubMed2004

S(+)-ketamine as an analgesic adjunct reduces opioid consumption after cardiac surgery.

There are no studies evaluating S(+)-ketamine for pain management after sternotomy. In this prospective, randomized, double-blind, placebo-controlled clinical trial, we evaluated the efficacy and feasibility of S(+)-ketamine as an adjunctive analgesic after cardiac surgery. Ninety patients scheduled for elective coronary artery bypass grafting (CABG) were randomized to receive either a 75 microg/kg bolus of S(+)-ketamine followed by a continuous infusion of 1.25 microg . kg(-1) . min(-1) for 48 h (n = 44) or placebo (normal saline bolus and infusion) (n = 46). From the time of tracheal extubation, patients could access an opioid (oxycodone) via a patient-controlled analgesia device, and the cumulative oxycodone doses were measured over 48 h. Pain was evaluated on a visual analog scale three times daily. The quality of recovery, patient satisfaction with pain management, and adverse effects were recorded. The cumulative oxycodone consumption during the first 48 postoperative hours was less in the S(+)-ketamine group (103 +/- 44 mg) than in the placebo group (125 +/- 45 mg; mean difference, 22 mg; 95% confidence interval for the difference, 3-40 mg; P = 0.023). Pain scores did not differ between the groups at rest (P = 0.17) or during a deep breath (P = 0.23). Patient satisfaction was superior in S(+)-ketamine-treated patients: 26 (60%) of 44 in the S(+)-ketamine group compared with 16 (35%) of 46 in the placebo group were very satisfied with the analgesic management (P = 0.032). Nausea and vomiting were the most common adverse events, with similar frequencies in both groups. Four patients in the S(+)-ketamine group developed transient hallucinations during the infusion, versus none in the placebo group. In conclusion, small-dose S(+)-ketamine decreased opioid consumption in CABG patients during the first 48 h after surgery.

Aged↗

PubMed1987

Efficacy of diclofenac in a single prophylactic dose in postoperative pain.

Prophylactic diclofenac (Voltaren) in postoperative pain was studied in 60 surgical patients who underwent either abdominal (30 patients) or superficial (30 patients) surgery. During anaesthesia, no analgesic or narcotic drugs were given. Immediately after surgery, an intravenous infusion of 100 ml normal saline or saline with 75 mg of diclofenac was administered over 10 minutes under double-blind randomized conditions. The 2-hour study period was started when the patients complained of pain or half an hour after the end of anaesthesia. For pain relief during the study period, 4 mg of oxycodone was repeatedly given on demand. The initial mean pain intensity values were significantly higher after abdominal surgery than after superficial surgery but there were no statistically significant differences between diclofenac and placebo groups. The mean amount of oxycodone required after diclofenac was not significantly lower than after placebo (10.9 +/- 1.9 mg vs. 13.1 +/- 1.4 mg after abdominal surgery and 3.2 +/- 0.8 mg vs. 4.0 +/- 1.2 mg after superficial surgery). The pain relief obtained with oxycodone was similar after diclofenac and placebo. According to the present results, prophylactic use of diclofenac does not significantly reduce the need for narcotic analgesics in the immediate postoperative phase in general surgery.

Adult↗

PubMed2003

The difficulties of ambulatory interscalene and intra-articular infusions for rotator cuff surgery: a preliminary report.

PURPOSE: Rotator cuff repair may result in severe postoperative pain. We compared a continuous intra-articular infusion to a continuous interscalene block with ropivacaine for patients undergoing outpatient rotator cuff repair. METHODS: Seventeen patients were randomized to one of two groups: 1) interscalene block with 0.5% ropivacaine (40 mL) followed by a postoperative intra-articular infusion or; 2) interscalene block with 0.5% ropivacaine (40 mL) followed by a postoperative continuous interscalene infusion. Infusions were 0.2% ropivacaine at 10 mL x hr(-1) for both groups. Infusions were maintained for 48 hr. Patients were discharged on the day of surgery. Verbal analogue pain scores (VAS) and postoperative oxycodone consumption were measured for 48 hr. RESULTS: Eight patients (47%; four in each group) had side effects or logistical problems complicating care. The mean VAS scores at rest and with movement in the postanesthesia care unit and at 12 hr, 24 hr, and 48 hr were not different (P > 0.1). Inadequate analgesia was reported in 50-75% of all study patients. Time until first oxycodone use was similar between groups 829 min +/- 432 (interscalene) and 999 min +/- 823 (intra-articular; P = 0.6). Total oxycodone consumption was also similar 49 mg +/- 48 and 59 mg +/- 51 (P = 0.7), respectively. CONCLUSIONS: This study demonstrates the difficulties of ambulatory interscalene and intra-articular infusion for rotator cuff surgery. The high VAS scores and need for additional medical care suggest that intra-articular administration may not be reasonable for this magnitude of surgery. Further refinement of the perineural local anesthetic infusion is necessary to consistently provide analgesia after ambulatory rotator cuff surgery.

Amides↗

PubMed2001

Economic evaluation of the fentanyl transdermal system for the treatment of chronic moderate to severe pain.

The fentanyl transdermal system (Duragesic) is an opioid analgesic indicated for the management of chronic moderate to severe pain. The purpose of this analysis is to estimate its economic value compared to two long-acting oral opioids. A cost-utility analysis was performed using a three-phased decision analytic model. The transdermal system had the highest expected cost during the first year of therapy ($2,491), moderately higher than the cost of a year of therapy with controlled-release morphine ($2,037) or controlled-release oxycodone ($2,307). The system also had the highest expected number of quality-adjusted life-days (QALDs) (244 compared to 236 for morphine and 231 for oxycodone), despite conservative assumptions. The fentanyl transdermal system achieved incremental cost-utility ratios of $20,709 (vs. morphine) and $5,273 (vs. oxycodone) per quality-adjusted life year (QALY) gained. In a conservative modeled analysis, the fentanyl transdermal system led to increased QALDs at a nominal increased cost. In the absence of head-to-head clinical trials, models help clarify cost and outcome trade-offs and provide a consistent theoretical framework for use by individual decisionmakers.

Administration, Cutaneous↗

PubMed1996

Evaluation of the usefulness of intrathecal bupivacaine infusion for analgesia after hip and knee arthroplasty.

Spinal anaesthesia in 47 ASA I-III patients was induced with 0.5% bupivacaine 2 ml via a 28-gauge spinal catheter (L3-4 interspace) and 0.5-ml increments were given if needed before or during hip or knee arthroplasty. Intrathecal 24-h infusions consisted of 0.5% bupivacaine 0.4 ml h-1 (2 mg h-1) (n = 12), 0.5% bupivacaine 0.2 ml h-1 (1 mg h-1) (n = 12) or saline (n = 11) (12 exclusions). Patients received oxycodone 0.1-0.14 mg kg-1 i.m. for rescue analgesia. Infusion of bupivacaine 2 mg h-1 provided significantly better postoperative analgesia (19 oxycodone doses per group in 24 h) compared with bupivacaine 1 mg h-1 (36 doses of oxycodone per group) and saline (52 doses per group) (P < 0.05). Five patients in the bupivacaine 2-mg h-1 group and none in the other groups had measurable sensory block 24 h after the infusion was started. Three patients in the bupivacaine 2-mg h-1 group, two with concomitant arterial hypotension, and one patient in the bupivacaine 1-mg h-1 group experienced an increase in block on the ward. The incidence of nausea and vomiting was similar in all groups. Although an effective analgesic, intrathecal infusion of bupivacaine 2 mg h-1 cannot be recommended for routine pain relief because of the risk of increasing spinal block. Technical problems (19%) also reduced the overall efficacy of the continuous intrathecal analgesic regimen.

Analgesia↗

PubMed2002

Simultaneous quantitation of opioids in blood by GC-EI-MS analysis following deproteination, detautomerization of keto analytes, solid-phase extraction, and trimethylsilyl derivatization.

Seven opioid analytes including codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, and oxymorphone were detected in postmortem blood (n > 1000). Two milliliters of specimen was deproteinated with approximately 2.5 mL of methanol and derivatized with hydroxylamine before solid-phase extraction and derivatization with BSTFA + 1% TMCS. Extracts were assayed by gas chromatography-electron impact-mass spectrometry utilizing selected ion mode. One-microliter aliquots were injected onto an HP-1MS capillary column (30 m x 0.25-mm i.d., 0.25 microm) with a helium linear velocity of 62 cm/s. Temperature programming began at 160 degrees C (hold 0 min), then increased at rates of 35 degrees C/min to 195 degrees C, 5 degrees C/min to 240 degrees C, and 30 degrees C/min to 300 degrees C (hold 2 min) resulting in a total run time of 14-min. Quantitative determinations were based on the ratios of the analyte peak areas to the corresponding deuterated analogues. Calibration curves were linear for the following concentrations: 10-500 ng/mL (6-AM), 100-2000 ng/mL (oxycodone), and 50-1000 ng/mL (all other opioids). LOQs ranged from 5 ng/mL (6-AM) to 20 ng/mL (oxycodone). Between-run precision yielded CVs ranging from 2.79% to 5.34% (n = 12). These data suggest that methanolic deproteination and dual derivatization improve separation and simultaneous quantitation of seven opioid analytes in difficult matrices.

Forensic Medicine↗

PubMed1987

Postoperative pain relief and bupivacaine plasma levels during continuous interscalene brachial plexus block.

Interscalene brachial plexus block was performed on 40 patients for prophylactic pain relief after shoulder surgery. A dose of 1.25 mg/kg of 0.5% bupivacaine was injected for the block (Group 1) and continued with an infusion of 0.25% bupivacaine 0.25 mg/kg/h (Group 2). If the postoperative analgesia was insufficient, the patients received i.m. oxycodone 0.15 mg/kg. In Group 1, one patient managed without oxycodone supplementation during the 24-h observation period compared with eight patients in Group 2 (P less than 0.01). The rest of the patients received 3.8 +/- 1.6 doses (Group 1) and 2.5 +/- 1.2 doses (Group 2) of oxycodone (P less than 0.05). At 30 min, the mean bupivacaine plasma concentration was 1.0 microgram/ml in Group 1 and 0.9 microgram/ml in Group 2. The mean plasma level of bupivacaine increased from 0.7 microgram/ml after 180 min to 1.1 micrograms/ml (P less than 0.01) after 24 h of infusion, providing some evidence of accumulation during infusion. The dizziness and confusion experienced by three patients could be associated with the local anaesthetic, as they obtained relief after the infusion was stopped.

Adolescent↗

PubMed2006

Geographic variation in the prescription of schedule II opioid analgesics among outpatients in the United States.

OBJECTIVE: To measure geographic variation in opioid use in a large, commercially insured, outpatient population in the United States. DATA SOURCES: Outpatient prescription drug claims database of a national pharmaceutical benefit manager for 7,873,337 subjects with at least one prescription drug claim in 2000. STUDY DESIGN: We measured the period prevalence of claims for opioid analgesics and controlled-release oxycodone at the state level. We measured geographic variation using the weighted coefficient of variation and systematic component of variation. In county-level multivariable regression, we explored associations between potential explanatory variables and claims for opioid analgesics and controlled-release oxycodone. PRINCIPAL FINDINGS: A total of 567,778 (64.2 per 1,000 total claims) were for oral opioid analgesics. Claim rates by state ranged from <20 to >100 claims per 1,000 total claims. States with long-standing prescription monitoring programs had among the lowest rates. In the county-level data, presence of a statewide prescription monitoring program and proportions of the population aged 15-24 and 65 years and older were independently and negatively associated with claim rates for all opioid analgesics. Surgeons per 1,000, proportion of the population reporting illicit drug use, and proportion who were female were independently and positively associated with claim rates for all opioid analgesics. Only the proportion of the population aged 25-34 and number of surgeons per 1,000 were independently and positively associated with claim rates for oxycodone. CONCLUSIONS: Claim rates for opioid analgesics vary significantly by state. Presence of a statewide prescription monitoring program is associated with lower claim rates at the county level. Future research should use individual-level data to assess whether these findings reflect a reduction in abuse and diversion or suboptimal treatment of pain.

Adolescent↗

PubMed2004

Trends in medical use and abuse of sustained-release opioid analgesics: a revisit.

OBJECTIVE: Previous literature suggests that increases in the medical use of opioids over the early 1990s did not contribute to increased morbidity secondary to opioid abuse. Our objective was to evaluate the period 1997-2001 to analyze trends in medical use and medical abuse of three classes of opioid analgesics that are commonly used in sustained-release formulations: fentanyl, morphine, and oxycodone. DESIGN AND SETTING: A retrospective analysis of the Drug Abuse Warning Network (DAWN) database and the Automation of Reports and Consolidated Orders System (ARCOS) database for the years 1997-2001 was used for this study. RESULTS: The analysis of the DAWN database showed that there was an 83.5% increase in all opioid analgesic mentions from 1997 to 2001. Mentions involving any fentanyl compound increased 249.8%, any morphine compound increased 161.8%, and any oxycodone-containing compound increased 267.3%. Mentions of each of these three classes of opioids remained less than 2% of all total drug mentions per year for each year studied. Medical use of the selected opioid classes, as reported in the ARCOS database and measured by grams distributed, all increased substantially (fentanyl 151.2%, morphine 48.8%, oxycodone 347.9%). CONCLUSION: Using this method of analysis, the rates of drug abuse, and resultant morbidity secondary to the use of opioid analgesics, remain low in spite of the increase in medical use of these substances.

Adolescent↗