Ratings Of Withdrawal Symptoms Research Articles

Patient-Reported Symptoms during Ibrutinib Holds: A Withdrawal Syndrome

Background:The Bruton tyrosine kinase (BTK) inhibitor ibrutinib recently became the first approved therapy for patients with symptomatic Waldenström macroglobulinemia (WM). The management of ibrutinib-related toxicities, such as bleeding and others, are often managed with temporary interruption of therapy. We observed that some WM patients who held ibrutinib developed symptoms during the time they were holding ibrutinib, which then resolved promptly after ibrutinib reinitiation. Our study aims at describing this “ibrutinib withdrawal” phenomenon.Methods: We identified patients seen at our institution between May 2012 and April 2017 who met clinicopathological criteria for WM, and received ibrutinib therapy. Medical files were manually reviewed to identify patients who reported new-onset symptoms occurring during a temporary hold of ibrutinib therapy. Pertinent clinical data were gathered. Patient characteristics are summarized descriptively. Univariate association with withdrawal symptoms was evaluated with logistic regression models.Results: A total of 189 patients with WM who started ibrutinib were identified; 100 patients (53%) have not held ibrutinib, and 89 (47%) held ibrutinib at some point during therapy. The median time on ibrutinib therapy in patients who held ibrutinib was 23 months (95% CI 13-30 months) and 10 months (95% CI 7-12 months) in patients who did not hold ibrutinib. There were no differences between the patients who held and did not hold ibrutinib with regards to age at WM diagnosis, age at ibrutinib initiation, sex, hemoglobin, platelet count, beta-2-microglobulin (B2M), serum IgM, bone marrow involvement, CXCR4 status, prior treatment and time between WM diagnosis and ibrutinib initiation (p≥0.05 for all factors). From the patients who held ibrutinib, 69 (78%) did not experience withdrawal symptoms and 20 (22%) did. Of the patients who experienced withdrawal symptoms, 17 (85%) were receiving ibrutinib in the relapsed/refractory setting. All patients were holding ibrutinib for the first time since treatment initiation. The median drug hold length was 7 days (range 3-33 days). Reasons for holding ibrutinib included: procedure/surgery (n=12; 60%), toxicity (n=6; 30%), drug interaction (n=1; 5%), and patient choice (n=1; 5%). The median time to symptom development was 2 days (range 0-5 days) from the start of the drug hold. Patient-reported symptoms included: fever (n=16; 80%), body aches (n=6; 30%), chills (n=5; 20%), night sweats (n=5; 20%), headache (n=4; 20%), fatigue (n=2; 10%), arthralgias (n=2; 10%), and weakness (n=1; 5%). There were no differences between patients who became symptomatic and remained asymptomatic during ibrutinib hold with regards to age at WM diagnosis, age at ibrutinib initiation, sex, hemoglobin, platelet count, B2M, bone marrow involvement, CXCR4 status, prior treatment, time from WM diagnosis and ibrutinib initiation and time on ibrutinib (p≥0.05 for all factors). Patients with serum IgM >4,000 mg/dl had a lower proportion of withdrawal symptoms than patients with serum IgM <4,000 mg/dl (9% vs. 30%; p=0.02). The rates of very good partial response (VGPR), partial response (PR), minor response (MR) and no response (NR) to ibrutinib were 16% (n=13), 57% (n=108), 22% (n=41) and 5% (n=9), respectively. No withdrawal symptoms were reported in patients with MR or NR. The proportion of patients with withdrawal symptoms was higher in patients who achieved VGPR (46%) than in patients who achieved PR (25%). Four patients with fever were admitted to the hospital; no infectious etiology was identified. All patients reported resolution of symptoms the same day ibrutinib was restarted following the drug hold. Nine patients had subsequent drug holds, and reported recurrence of the same symptoms during the hold period. Two patients known to develop these symptoms were treated with corticosteroids during a subsequent hold and reported symptomatic relief.Conclusion: We describe patient-reported symptoms that develop in about 20% of WM patients who held ibrutinib therapy. The rate of withdrawal symptoms is lower in patients who started ibrutinib with IgM levels >4,000 mg/dl (9%), and higher in patients who had achieved VGPR on ibrutinib (46%). Such symptoms ensue within 2 days of hold and resolve rapidly following reinitiation of therapy. Clinicians should be aware of this phenomenon which may represent an ibrutinib withdrawal syndrome. DisclosuresCastillo:Millennium: Research Funding; Abbvie: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Treon:Pharmacyclics: Consultancy, Research Funding.

Analgesia and Sedation Protocol for Mechanically Ventilated Postsurgical Children Reduces Benzodiazepines and Withdrawal Symptoms-But Not in All Patients.

Background We demonstrated recently that the implementation of a nurse-driven analgesia and sedation protocol (pediatric analgesia and sedation protocol [pASP]) for mechanically ventilated nonpostsurgical patients reduces the total dose of benzodiazepines and the withdrawal symptoms significantly. It has not been investigated if these results can also be expected in the group of patients undergoing surgery. Objectives To evaluate the effects of the pASP in mechanically ventilated postsurgical children regarding drug dosage, duration of mechanical ventilation, length of stay, and rate of withdrawal symptoms. Methods This is a two-phase prospective observational control study. The preimplementation group was managed by the physician's order and the postimplementation group was managed with the pASP including COMFORT-B, nurse interpretation of sedation, and Sophia observation withdrawal symptoms scale scoring. Measurements and Main Results One hundred and sixteen patients were included before and one hundred and ten patients after implementation. The pASP had no effect on length of pediatric intensive care unit stay or duration of mechanical ventilation. The protocol reduced total (5.0 mg/kg [0.5-58.0] vs 4.0 mg/kg [0.0-47.0]; p = 0.021) and daily doses (4.4 mg/kg/d [1.1-33.9] vs 2.9 mg/kg/d [0.0-9.9]; p < 0.001) of benzodiazepines significantly. No difference was observed in total and daily doses of opioids (5.0 mg/kg [0.1-67.0] vs 3.0 mg/kg [0.1-71.0]; p = 0.81) and (0.7 mg/kg/d [0.0-7.0] vs. 0.8 mg/kg/d [0.0-3.7]; p = 0.35), respectively. Rate of withdrawal symptoms was significantly lower after implementation (35.3 vs 20.0%; p = 0.01), but not in patients after solid organ transplantation or oncological patients. Conclusion The nurse-driven analgesia and sedation protocol is an effective procedure to reduce the total doses of benzodiazepines and occurrence of withdrawal symptoms in postsurgical children, which are naïve to opioids or benzodiazepines.

The Role of Cystine-Glutamate Exchange in Nicotine Dependence in Rats and Humans

The present study determined if, akin to cocaine, nicotine self-administration in rats induces adaptations in the expression of glutamate transporters and cystine-glutamate exchangers in brain nuclei implicated in reinforcement and if treating cigarette smokers with a drug that restores cystine-glutamate exchange affects the number of cigarettes smoked. Rats self-administered nicotine intravenously for 12 hours/day or received nicotine through osmotic minipumps for 21 days. Somatic signs of withdrawal were measured and immunoblotting was performed 12 hours after the last nicotine exposure to determine if the catalytic subunit of the cystine-glutamate exchanger, xCT, or the glial glutamate transporter, GLT-1, were altered in the ventral tegmental area (VTA), nucleus accumbens, prefrontal cortex, or amygdala. For the smoking reduction study in humans, nicotine-dependent smokers were treated for 4 weeks with N-acetylcysteine (2400 mg daily) to promote cystine-glutamate exchange or placebo. Participants provided weekly ratings of withdrawal symptoms, craving, and carbon monoxide (CO) measurements and logged daily cigarette and alcohol use. Rats receiving nicotine via self-administration or minipumps displayed somatic signs of withdrawal, but only nicotine self-administering rats showed decreased xCT expression in the nucleus accumbens and VTA and decreased GLT-1 expression in the nucleus accumbens. Human smokers treated with N-acetylcysteine reported a reduction in cigarettes smoked, and there was no effect of N-acetylcysteine on estimates of CO levels, craving, or withdrawal. These results indicate that the cystine-glutamate exchanger and the glial glutamate transporter are downregulated after nicotine self-administration, and augmenting exchanger activity with N-acetylcysteine reduced the number of cigarettes smoked in nicotine-dependent individuals.

Severity of withdrawal symptoms as a predictor of outcome of an attempt to quit smoking

In 227 smokers' clinic clients who managed at least one week of abstinence, ratings of withdrawal symptoms were used to predict subsequent return to smoking. Depression, time spent with urges to smoke, and difficulty not smoking during the first week of abstinence were significantly associated with lapse back to smoking during the second week. Depression and difficulty not smoking during the second week significantly predicted smoking status during the third week. No withdrawal symptoms during the third week were associated with a return to smoking during the fourth week. The predictive power of withdrawal symptoms was over and above that of smoke intake and dependence. The findings provide some support for the view that reduction of withdrawal symptoms may be a worthwhile target in programmes for helping smokers to quit.

Time course of cigarette widhdrawal symptoms while using nicotine gum

Ratings of withdrawal symptoms were provided at weekly intervals by 147 smokers clinic clients who managed complete abstinence for 4 weeks. The ratings followed a similar temporal pattern regardless of amount of nicotine gum used. Irritability, depression, difficulty concentrating and restlessness peaked in the 1st week or two and returned to baseline by week 4. Hunger was more persistent. Craving was reported to be the most troublesome withdrawal symptom at first, although by the 4th week hunger was cited almost as often. Across all subjects, evenings were cited most often as the worst time of day for craving but among heavier smokers and those who used more nicotine gum mornings were considered worst.

Time course of cigarette withdrawal symptoms during four weeks of treatment with nicotine chewing gum.

Ratings of withdrawal symptoms were obtained from 52 Smokers Clinic clients who abstained throughout a four week group treatment programme involving use of nicotine chewing gum. Mean ratings of irritability, depression, hunger, restlessness, and inability to concentrate were significantly higher in the first week of abstinence than at baseline, although only a minority of smokers experienced severe withdrawal symptoms. Disturbance of mood and concentration returned to baseline within four weeks while increases in hunger persisted. The average amount of time spent with the urge to smoke started to decline early in treatment, but the average strength of urges and overall difficulty not smoking did not decline until the fourth week. At the end of treatment 35% were still experiencing strong urges to smoke and 23% reported finding it difficult keeping themselves from smoking. The findings have practical implications for preparing smokers for cessation with the aid of nicotine gum.