Brief Report
Baclofen‐Induced Edema in Alcohol Use Disorders
The Journal of Clinical Pharmacology 54(4) 478–481 © 2013, The American College of Clinical Pharmacology DOI: 10.1002/jcph.233
Camille Bence, MD1,3, Olivier Cottencin, MD, PhD1,2,3, Sylvie Deheul, MD3,4, Sophie Gautier, PharmD, PhD3,4, Régis Bordet, MD, PhD3,4, and Benjamin Rolland, MD, PhD1,3,4 Keywords baclofen, edema, alcoholism, adverse effects, off‐label use, drug monitoring, pharmacovigilance
Although alcohol use disorders (AUDs) constitute an important burden of disease in Europe,1 the currently approved medications remain insufficiently efficacious,2 and off‐label drugs may be required. Baclofen is a gamma‐amino butyric acid type B (GABA‐B) receptor agonist that was originally approved for spasticity.3 In this indication, baclofen can be delivered orally or intrathecally. Recently, baclofen 30 mg/day has been reported to be a promising therapeutic option for AUDs.4,5 Moreover, a baclofen dose–response effect has been suspected in AUDs, and high‐dose baclofen (HDB), that is, more than 80 mg/day, is increasingly being used in current clinical practice.6,7 However, the global tolerability of baclofen at such doses remains largely unexplored. Some types of adverse drug reactions (ADRs) may occur at high doses and may even be preferentially induced in patients with persistent alcohol abuse.8 Due to the lack of data, several addiction centers of the Nord‐Pas‐de‐Calais region, France, have joined with the regional department of pharmacovigilance to create a system named CAMTEA, which delivers HDB prescriptions for AUDs only under strict monitoring, including follow‐up by pharmacovigilance specialists, to better spot ADRs.8 Such a system may thus detect ADRs that were not described with the oral form at a dose of 80 mg/day or in patients without an AUD. Recently, a national pharmacovigilance report in France found that off‐label baclofen could induce previously unknown ADRs.9 Notably, this identified lower extremity edema. However, in this document, ADRs were not assessed using validated methods for determining causality. We report herein the occurrence of lower extremity edema in three patients with persistent AUDs during their off‐label treatment with baclofen. In each case, the causality of baclofen in triggering edema was assessed using Naranjo’s scale,10 which is a validated tool for determining the likelihood that a given drug induced a specific ADR.11
Case Series Case 1 Case 1 was a 51‐year‐old female patient with no previous medical history, notably no liver disease. The DSM‐IV‐ TR criteria for alcohol abuse had been present for twelve years, with an average alcohol consumption of 120 g/day. Off‐label baclofen was introduced slowly to reduce the drinking level. The patient was on no other medication. After 5 weeks of baclofen treatment, when the patient reached a dose of 75 mg/day, the family physician contacted our team to report the occurrence of bilateral pitting and painful ankle edema. Her alcohol consumption was then 70 g/day. Venous Doppler ultrasound examination found no varicose veins or signs of deep venous thrombosis. Electrocardiography was normal. Laboratory examinations only revealed moderate hepatic cytolysis, but no liver or kidney insufficiency: AST 34 U/L, ALT 16 U/L, GGT 156 U/L, bilirubin 17 mmol/L (i.e., 1 mg/ dL), albumin 7.6 mmol/L (i.e., 5.3 g/dL), urea 5.5 mmol/L (i.e., 15.4 mg/dL), creatinine 66.3 mmol/L (i.e., 0.8 mg/ dL). Because no cause for such edema was found, baclofen was discontinued within 1 week. The edema diminished quickly and disappeared after four days. Baclofen was never reintroduced. No other episode of edema was observed during the following 6 months.
1
Department of Addiction Medicine, CHU Lille, Lille cedex, France Univ Lille Nord de France, Lille cedex, France 3 Dispositif CAMTEA, Lille cedex, France 4 Department of Pharmacology and Pharmacovigilance, CHU Lille, Lille cedex, France 2
Submitted for publication 16 September 2013; accepted 12 November 2013. Corresponding Author: Dr. Benjamin Rolland, Service d’Addictologie, Hôpital Fontan2, rue André Verhaeghe, CHRU de Lille, 59037 Lille cedex, France Email: [email protected]
479
Bence et al
Case 2 Case 2 was a 60‐year‐old male patient with a medical history including cluster headache that was stabilized with lithium carbonate 250 mg/day, tobacco‐induced chronic bronchitis and sleep apnea. The patient met the DSM‐IV‐ TR criteria for alcohol dependence, which had been evolving for more than ten years. The initial drinking level was 300–400 g/day of alcohol. Previous treatments with naltrexone and acamprosate were ineffective. Off‐label baclofen was introduced at slowly increasing doses. After 6 months of treatment, the baclofen dose was 240 mg/day, and his average alcohol consumption had fallen to 40 g/ day of alcohol. The patient wished to progressively stop consuming alcohol, and he was thus willing to continue increasing the baclofen dose. However, 1 week after he reached 250 mg/day of baclofen, the patient presented with severe, bilateral, painful and pitting ankle edema. There was no clinical sign of cardiac insufficiency. Laboratory examinations found no abnormality: sodium 143 mEq/L, AST 19 U/L, ALT 20 U/L, GGT 101 U/L, Alk phos 76 U/L, bilirubin 13.8 mmol/L (0.81 mg/dL), albumin 6.42 mmol/L (i.e., 4.43 g/dL), urea 4.8 mmol/L (i.e., 13.5 mg/dL), creatinine 79.7 mmol/L (i.e., 0.9 mg/dL), lithium 0.5 mEq/L. The declared alcohol consumption was still 40 g/day. The baclofen dose was reduced as a diagnostic test. After 6 days, the dose was reduced to 220 mg/day, and the edema disappeared completely. The baclofen dose was progressively decreased. Today, more than 6 months after the edema disappeared, the patient is being treated with 90 mg/day of baclofen, and he is abstinent from alcohol.
Case 3 Case 3 was a 35‐year‐old female patient with a medical history of arterial hypertension and bipolar mood disorder. She was receiving stable medication consisting of amlodipine 10 mg/day, lithium carbonate controlled‐ release 400 mg/day and venlafaxine 37.5 mg/day. She had presented the DSM‐IV‐TR criteria for alcohol‐ dependence for the last 3 years. She reported a daily alcohol consumption of 80 g/day. Baclofen was therefore introduced. After 2 months of treatment, the baclofen dose was 100 mg/day, and her daily reported alcohol consumption was unchanged. Three days after the baclofen dose had been increased to 120 mg/day, bilateral ankle edema occurred. The edema was pitting but painless. A clinical examination found no signs of cardiac, renal, or hepatic insufficiency. Laboratory parameters were normal: sodium 140 mEq/L, AST 24 U/L, ALT 20 U/L, GGT 26 U/L, bilirubin 15.5 mmol/L (0.9 mg/dL), albumin 6.8 mmol/L (i.e., 4.7 g/dL), urea 5.33 mmol/L (i.e., 14.9 mg/dL), creatinine 69.9 mmol/L (i.e., 0.8 mg/dL), lithium 1.1 mEq/L. The baclofen dose was reduced to 90 mg/day within 1 week, and a quick regression of the edema followed. The same dose was maintained for two months, with no effect on her alcohol consumption, and was then discontinued. Assessment of Baclofen Causality The causality of baclofen was assessed for each of the three cases using Naranjo’s algorithm.10 The details of the calculation are presented in Table 1.
Table 1. Causality Scoring of Baclofen Using Naranjo’s Algorithm10 for Each of the Three Cases Questions 1. Are there previous conclusive reports on this reaction? Yes (þ1) No (0) Do not know or not done (0) 2. Did the adverse event appear the suspected drug was administered? Yes (þ2) No (1) Do not know or not done (0) 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? Yes (þ1) No (0) Do not know or not done (0) 4. Did the adverse reaction reappear when the drug was readministered? Yes (þ2) No (1) Do not know or not done (0) 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? Yes (‐1) No (þ2) Do not know or not done (0) 6. Did the reaction reappear when a placebo was given? Yes (1) No (þ1) Do not know or not done (0) 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? Yes (þ1) No (0) Do not know or not done (0) 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? Yes (þ1) No (0) Do not know or not done (0) 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? Yes (þ1) No (0) Do not know or not done (0) 10. Was the adverse event confirmed by any objective evidence? Yes (þ1) No (0) Do not know or not done (0) Total score Scoring: >9 ¼ definite adverse drug reaction (ADR), 5–8 ¼ probable ADR, 1–4 ¼ possible ADR, 0 ¼ doubtful ADR.
Case 1 Case 2 Case 3 þ1
þ1
þ1
þ2
þ2
þ2
þ1
0
0
0
0
0
þ2
1
1
0
0
0
0
0
0
0
þ1
þ1
0
0
0
þ1
þ1
þ1
7
4
4
480 The response patterns were not similar in the three cases. We considered that there were previous conclusive reports on baclofen‐induced edema because this ADR was mentioned in the recent French pharmacovigilance report on baclofen (“þ1” for question 1). Edema occurred after baclofen was introduced and disappeared quickly after baclofen was discontinued (“þ2” for question 2 and “þ1” for question 3). In all three of the cases, there was no attempt to readminister baclofen (“0” for question 4), no attempt to test a placebo (“0” for question 6), and no dosing of baclofen in the blood or any other fluid. For Case 1, there was no plausible alternative cause of edema (“þ2” for question 5), whereas for Cases 2 and 3, both lithium and amlodipine are theoretically alternative causes for edema in the patients12,13 (“1” for question 5). The final causality score was “7” for Case 1, indicating that the role of baclofen in inducing the edema was “probable.” It was “4” for Cases 2 and 3, determining a “possible” causality of baclofen.
Discussion Ankle edema was reported as a possible albeit anecdotal baclofen‐induced ADR by the Food and Drug Administration.14 Regarding the AUD‐related off‐label use of baclofen, a recent pharmacovigilance report found that edema appeared more frequently.9 However, the causality level was not available in that report. The three cases herein constitute the first description of baclofen‐induced edema for which the causality was determined using a validated method. In our cohort of 202 subjects treated with baclofen for AUDs, a total 10 subjects reported edema, which leads to rough incidence rate of 5%. Baclofen‐induced edema was absent from previous literature on the approved use of baclofen, which suggests that edema could be more frequent or more noticeable at high doses and in patients with AUDs. In two of the three cases, the baclofen dose was above 80 mg/day and thus constituted high‐dose prescriptions. This could suggest that baclofen‐induced edema may appear above a certain dose threshold, although it may also be very patient dependent. Moreover, in all three cases, the patients were still drinking an abusive amount of alcohol. Therefore, co‐ exposure to both baclofen and alcohol could constitute a cumulative risk factor for edema. However, such etiological hypotheses cannot be addressed through case descriptions and should be assessed in future pharmacoepidemiological studies on ADRs induced by off‐label prescriptions of baclofen to treat AUDs. The pharmacological mechanisms through which baclofen may contribute to the occurrence of peripheral edema remain unknown. However, it has already been demonstrated that baclofen may enhance edematous reactions by increasing the plasma exudation response
The Journal of Clinical Pharmacology / Vol 54 No 4 (2014)
to diverse signaling molecules, such as substance P, histamine and 5‐hydroxytryptamine.15 However, this process is considered indirect, through the central activation of the adrenergic system by baclofen, which in turn may precipitate peripheral pro‐edematous reactions.15 Interestingly, high doses of baclofen have been reported to cause such a reaction in rats.16 Should this finding also be valid in humans, it may explain the preponderance of high doses of baclofen in the cases described herein. Moreover, alcohol abuse induces endothelial dysfunction, which potentiates local pro‐ inflammatory reactions17 and enhances vascular permeability.18 Consequently, pharmacological findings appear to support the clinical observation that baclofen‐induced peripheral edema is more likely to occur at higher doses and in the presence of co‐exposure to high amounts of alcohol. Declaration of Conflicting Interests Camille Bence, Benjamin Rolland, and Olivier Cottencin are associate investigators in the ALPADIR clinical trial, which is comparing baclofen versus placebo for the maintenance of abstinence in alcohol dependence.
References 1. Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol‐use disorders. Lancet. 2009;373:2223–2233. 2. Bouza C, Angeles M, Magro A, Muñoz A, Amate JM. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: A systematic review. Addiction. 2004;99:811–828. 3. Sachais BA, Logue JN, Carey MS. Baclofen, a new antispastic drug. A controlled, multicenter trial in patients with multiple sclerosis. Arch Neurol. 1977;34:422–428. 4. Addolorato G, Leggio L, Ferrulli A, et al. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol‐dependent patients with liver cirrhosis: Randomised, double‐blind controlled study. Lancet. 2007;370:1915–1922. 5. Leggio L, Garbutt JC, Addolorato G, Effectiveness and safety of baclofen in the treatment of alcohol dependent patients. CNS Neurol Disord Drug Targets. 2010;9:33–44. 6. Pastor A, Jones DML, Currie J. High‐dose baclofen for treatment‐ resistant alcohol dependence. J Clin Psychopharmacol. 2012;32: 266–268. 7. Rigal L, Alexandre‐Dubroeucq C, de Beaurepaire R, Le Jeunne C, Jaury P. Abstinence and “low‐risk” consumption 1 year after the initiation of high‐dose baclofen: A retrospective study among “high‐ risk” drinkers. Alcohol Alcohol. 2012;47:439–442. 8. Rolland B, Bordet R, Cottencin O. Alcohol‐dependence: The current French craze for baclofen. Addiction. 2012;107:848–849. 9. Agence Nationale de Sécurité du Médicament et des produits de santé (ANSM). Rapport du Comité Technique de Pharmacovigilance du 16 avril 2013 [Report from the Pharmacovigilance Technical Committee, April 6, 2013]. Available online at: http://ansm.sante.fr/ content/download/52485/676187/version/2/file/ CR_CT012013023_Pharmacovigilance.pdf (consulted on September 2, 2013). 10. Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther. 1981;30:239–245.
Bence et al 11. Agbabiaka TB, Savović J, Ernst E. Methods for causality assessment of adverse drug reactions: A systematic review. Drug Saf. 2008;31:21–37. 12. Demers R, Heninger G. Pretibial edema and sodium retention during lithium carbonate treatment. JAMA. 1970;214:1845–1848. 13. Andrésdóttir MB, van Hamersvelt HW, van Helden MJ, van de Bosch WJ, Valk IM, Huysmans FT. Ankle edema formation during treatment with the calcium channel blockers lacidipine and amlodipine: A single‐centre study. J Cardiovasc Pharmacol. 2000;35: (3 Suppl. 1):S25–S30. 14. Baclofen Official FDA information, side effects and uses. Available online at: http://www.drugs.com/pro/baclofen.html (consulted on September 2, 2013).
481 15. Walker SB, Chahl LA. The mechanism of enhancement of the neurogenic oedema response by baclofen. Eur J Pharmacol. 1980;62:27–34. 16. Chahl LA, Walker SB. The effect of baclofen on the cardiovascular system of the rat. Br J Pharmacol. 1980;69:631–638. 17. Shirpoor A, Salami S, Khadem‐Ansari MH, Heshmatian B, Ilkhanizadeh B. Long‐term ethanol consumption initiates atherosclerosis in rat aorta through inflammatory stress and endothelial dysfunction. Vascul Pharmacol. 2012;57:72–77. 18. Greiff L, Erjefält I, Wollmer P, Pipkorn U, Persson CG. Effects of histamine, ethanol, and a detergent on exudation and absorption across guinea pig airway mucosa in vivo. Thorax. 1991; 46:700–705.
Baclofen‐Induced Edema in Alcohol Use Disorders
The Journal of Clinical Pharmacology 54(4) 478–481 © 2013, The American College of Clinical Pharmacology DOI: 10.1002/jcph.233
Camille Bence, MD1,3, Olivier Cottencin, MD, PhD1,2,3, Sylvie Deheul, MD3,4, Sophie Gautier, PharmD, PhD3,4, Régis Bordet, MD, PhD3,4, and Benjamin Rolland, MD, PhD1,3,4 Keywords baclofen, edema, alcoholism, adverse effects, off‐label use, drug monitoring, pharmacovigilance
Although alcohol use disorders (AUDs) constitute an important burden of disease in Europe,1 the currently approved medications remain insufficiently efficacious,2 and off‐label drugs may be required. Baclofen is a gamma‐amino butyric acid type B (GABA‐B) receptor agonist that was originally approved for spasticity.3 In this indication, baclofen can be delivered orally or intrathecally. Recently, baclofen 30 mg/day has been reported to be a promising therapeutic option for AUDs.4,5 Moreover, a baclofen dose–response effect has been suspected in AUDs, and high‐dose baclofen (HDB), that is, more than 80 mg/day, is increasingly being used in current clinical practice.6,7 However, the global tolerability of baclofen at such doses remains largely unexplored. Some types of adverse drug reactions (ADRs) may occur at high doses and may even be preferentially induced in patients with persistent alcohol abuse.8 Due to the lack of data, several addiction centers of the Nord‐Pas‐de‐Calais region, France, have joined with the regional department of pharmacovigilance to create a system named CAMTEA, which delivers HDB prescriptions for AUDs only under strict monitoring, including follow‐up by pharmacovigilance specialists, to better spot ADRs.8 Such a system may thus detect ADRs that were not described with the oral form at a dose of 80 mg/day or in patients without an AUD. Recently, a national pharmacovigilance report in France found that off‐label baclofen could induce previously unknown ADRs.9 Notably, this identified lower extremity edema. However, in this document, ADRs were not assessed using validated methods for determining causality. We report herein the occurrence of lower extremity edema in three patients with persistent AUDs during their off‐label treatment with baclofen. In each case, the causality of baclofen in triggering edema was assessed using Naranjo’s scale,10 which is a validated tool for determining the likelihood that a given drug induced a specific ADR.11
Case Series Case 1 Case 1 was a 51‐year‐old female patient with no previous medical history, notably no liver disease. The DSM‐IV‐ TR criteria for alcohol abuse had been present for twelve years, with an average alcohol consumption of 120 g/day. Off‐label baclofen was introduced slowly to reduce the drinking level. The patient was on no other medication. After 5 weeks of baclofen treatment, when the patient reached a dose of 75 mg/day, the family physician contacted our team to report the occurrence of bilateral pitting and painful ankle edema. Her alcohol consumption was then 70 g/day. Venous Doppler ultrasound examination found no varicose veins or signs of deep venous thrombosis. Electrocardiography was normal. Laboratory examinations only revealed moderate hepatic cytolysis, but no liver or kidney insufficiency: AST 34 U/L, ALT 16 U/L, GGT 156 U/L, bilirubin 17 mmol/L (i.e., 1 mg/ dL), albumin 7.6 mmol/L (i.e., 5.3 g/dL), urea 5.5 mmol/L (i.e., 15.4 mg/dL), creatinine 66.3 mmol/L (i.e., 0.8 mg/ dL). Because no cause for such edema was found, baclofen was discontinued within 1 week. The edema diminished quickly and disappeared after four days. Baclofen was never reintroduced. No other episode of edema was observed during the following 6 months.
1
Department of Addiction Medicine, CHU Lille, Lille cedex, France Univ Lille Nord de France, Lille cedex, France 3 Dispositif CAMTEA, Lille cedex, France 4 Department of Pharmacology and Pharmacovigilance, CHU Lille, Lille cedex, France 2
Submitted for publication 16 September 2013; accepted 12 November 2013. Corresponding Author: Dr. Benjamin Rolland, Service d’Addictologie, Hôpital Fontan2, rue André Verhaeghe, CHRU de Lille, 59037 Lille cedex, France Email: [email protected]
479
Bence et al
Case 2 Case 2 was a 60‐year‐old male patient with a medical history including cluster headache that was stabilized with lithium carbonate 250 mg/day, tobacco‐induced chronic bronchitis and sleep apnea. The patient met the DSM‐IV‐ TR criteria for alcohol dependence, which had been evolving for more than ten years. The initial drinking level was 300–400 g/day of alcohol. Previous treatments with naltrexone and acamprosate were ineffective. Off‐label baclofen was introduced at slowly increasing doses. After 6 months of treatment, the baclofen dose was 240 mg/day, and his average alcohol consumption had fallen to 40 g/ day of alcohol. The patient wished to progressively stop consuming alcohol, and he was thus willing to continue increasing the baclofen dose. However, 1 week after he reached 250 mg/day of baclofen, the patient presented with severe, bilateral, painful and pitting ankle edema. There was no clinical sign of cardiac insufficiency. Laboratory examinations found no abnormality: sodium 143 mEq/L, AST 19 U/L, ALT 20 U/L, GGT 101 U/L, Alk phos 76 U/L, bilirubin 13.8 mmol/L (0.81 mg/dL), albumin 6.42 mmol/L (i.e., 4.43 g/dL), urea 4.8 mmol/L (i.e., 13.5 mg/dL), creatinine 79.7 mmol/L (i.e., 0.9 mg/dL), lithium 0.5 mEq/L. The declared alcohol consumption was still 40 g/day. The baclofen dose was reduced as a diagnostic test. After 6 days, the dose was reduced to 220 mg/day, and the edema disappeared completely. The baclofen dose was progressively decreased. Today, more than 6 months after the edema disappeared, the patient is being treated with 90 mg/day of baclofen, and he is abstinent from alcohol.
Case 3 Case 3 was a 35‐year‐old female patient with a medical history of arterial hypertension and bipolar mood disorder. She was receiving stable medication consisting of amlodipine 10 mg/day, lithium carbonate controlled‐ release 400 mg/day and venlafaxine 37.5 mg/day. She had presented the DSM‐IV‐TR criteria for alcohol‐ dependence for the last 3 years. She reported a daily alcohol consumption of 80 g/day. Baclofen was therefore introduced. After 2 months of treatment, the baclofen dose was 100 mg/day, and her daily reported alcohol consumption was unchanged. Three days after the baclofen dose had been increased to 120 mg/day, bilateral ankle edema occurred. The edema was pitting but painless. A clinical examination found no signs of cardiac, renal, or hepatic insufficiency. Laboratory parameters were normal: sodium 140 mEq/L, AST 24 U/L, ALT 20 U/L, GGT 26 U/L, bilirubin 15.5 mmol/L (0.9 mg/dL), albumin 6.8 mmol/L (i.e., 4.7 g/dL), urea 5.33 mmol/L (i.e., 14.9 mg/dL), creatinine 69.9 mmol/L (i.e., 0.8 mg/dL), lithium 1.1 mEq/L. The baclofen dose was reduced to 90 mg/day within 1 week, and a quick regression of the edema followed. The same dose was maintained for two months, with no effect on her alcohol consumption, and was then discontinued. Assessment of Baclofen Causality The causality of baclofen was assessed for each of the three cases using Naranjo’s algorithm.10 The details of the calculation are presented in Table 1.
Table 1. Causality Scoring of Baclofen Using Naranjo’s Algorithm10 for Each of the Three Cases Questions 1. Are there previous conclusive reports on this reaction? Yes (þ1) No (0) Do not know or not done (0) 2. Did the adverse event appear the suspected drug was administered? Yes (þ2) No (1) Do not know or not done (0) 3. Did the adverse reaction improve when the drug was discontinued or a specific antagonist was administered? Yes (þ1) No (0) Do not know or not done (0) 4. Did the adverse reaction reappear when the drug was readministered? Yes (þ2) No (1) Do not know or not done (0) 5. Are there alternative causes (other than the drug) that could on their own have caused the reaction? Yes (‐1) No (þ2) Do not know or not done (0) 6. Did the reaction reappear when a placebo was given? Yes (1) No (þ1) Do not know or not done (0) 7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic? Yes (þ1) No (0) Do not know or not done (0) 8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased? Yes (þ1) No (0) Do not know or not done (0) 9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure? Yes (þ1) No (0) Do not know or not done (0) 10. Was the adverse event confirmed by any objective evidence? Yes (þ1) No (0) Do not know or not done (0) Total score Scoring: >9 ¼ definite adverse drug reaction (ADR), 5–8 ¼ probable ADR, 1–4 ¼ possible ADR, 0 ¼ doubtful ADR.
Case 1 Case 2 Case 3 þ1
þ1
þ1
þ2
þ2
þ2
þ1
0
0
0
0
0
þ2
1
1
0
0
0
0
0
0
0
þ1
þ1
0
0
0
þ1
þ1
þ1
7
4
4
480 The response patterns were not similar in the three cases. We considered that there were previous conclusive reports on baclofen‐induced edema because this ADR was mentioned in the recent French pharmacovigilance report on baclofen (“þ1” for question 1). Edema occurred after baclofen was introduced and disappeared quickly after baclofen was discontinued (“þ2” for question 2 and “þ1” for question 3). In all three of the cases, there was no attempt to readminister baclofen (“0” for question 4), no attempt to test a placebo (“0” for question 6), and no dosing of baclofen in the blood or any other fluid. For Case 1, there was no plausible alternative cause of edema (“þ2” for question 5), whereas for Cases 2 and 3, both lithium and amlodipine are theoretically alternative causes for edema in the patients12,13 (“1” for question 5). The final causality score was “7” for Case 1, indicating that the role of baclofen in inducing the edema was “probable.” It was “4” for Cases 2 and 3, determining a “possible” causality of baclofen.
Discussion Ankle edema was reported as a possible albeit anecdotal baclofen‐induced ADR by the Food and Drug Administration.14 Regarding the AUD‐related off‐label use of baclofen, a recent pharmacovigilance report found that edema appeared more frequently.9 However, the causality level was not available in that report. The three cases herein constitute the first description of baclofen‐induced edema for which the causality was determined using a validated method. In our cohort of 202 subjects treated with baclofen for AUDs, a total 10 subjects reported edema, which leads to rough incidence rate of 5%. Baclofen‐induced edema was absent from previous literature on the approved use of baclofen, which suggests that edema could be more frequent or more noticeable at high doses and in patients with AUDs. In two of the three cases, the baclofen dose was above 80 mg/day and thus constituted high‐dose prescriptions. This could suggest that baclofen‐induced edema may appear above a certain dose threshold, although it may also be very patient dependent. Moreover, in all three cases, the patients were still drinking an abusive amount of alcohol. Therefore, co‐ exposure to both baclofen and alcohol could constitute a cumulative risk factor for edema. However, such etiological hypotheses cannot be addressed through case descriptions and should be assessed in future pharmacoepidemiological studies on ADRs induced by off‐label prescriptions of baclofen to treat AUDs. The pharmacological mechanisms through which baclofen may contribute to the occurrence of peripheral edema remain unknown. However, it has already been demonstrated that baclofen may enhance edematous reactions by increasing the plasma exudation response
The Journal of Clinical Pharmacology / Vol 54 No 4 (2014)
to diverse signaling molecules, such as substance P, histamine and 5‐hydroxytryptamine.15 However, this process is considered indirect, through the central activation of the adrenergic system by baclofen, which in turn may precipitate peripheral pro‐edematous reactions.15 Interestingly, high doses of baclofen have been reported to cause such a reaction in rats.16 Should this finding also be valid in humans, it may explain the preponderance of high doses of baclofen in the cases described herein. Moreover, alcohol abuse induces endothelial dysfunction, which potentiates local pro‐ inflammatory reactions17 and enhances vascular permeability.18 Consequently, pharmacological findings appear to support the clinical observation that baclofen‐induced peripheral edema is more likely to occur at higher doses and in the presence of co‐exposure to high amounts of alcohol. Declaration of Conflicting Interests Camille Bence, Benjamin Rolland, and Olivier Cottencin are associate investigators in the ALPADIR clinical trial, which is comparing baclofen versus placebo for the maintenance of abstinence in alcohol dependence.
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