Author's Accepted Manuscript
Pregabalin-relatedhypertriglyceridemia Udo Bonnet MD, Behnaz Taazimi MD, HeinzDieter Grabbe MD
PII: DOI: Reference:
S0033-3182(14)00056-5 http://dx.doi.org/10.1016/j.psym.2014.03.009 PSYM456
To appear in:
Psychosomatics
Cite this article as: Udo Bonnet MD, Behnaz Taazimi MD, Heinz-Dieter Grabbe MD, Pregabalin-relatedhypertriglyceridemia, Psychosomatics, http://dx.doi.org/ 10.1016/j.psym.2014.03.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Pregabalin-related hypertriglyceridemia
Udo Bonnet, MD1, Behnaz Taazimi, MD1, Heinz-Dieter Grabbe1, MD 1
Department of Psychiatry, Psychotherapy and Psychosomatics, Evangelisches
Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University of Duisburg/Essen, Germany Key words pregabalin, gabapentin, elevated triglycerides, metabolic syndrome
Corresponding author Prof. Dr. med. Udo Bonnet Klinik für Psychiatrie, Psychotherapie und Psychosomatik Evangelisches Krankenhaus Castrop-Rauxel Grutholzallee 21 44577 Castrop-Rauxel Germany Telephone number: (+49) 02305/1022858 Fax number: (+49) 02305/1022860 Email: [email protected]
Acknowledgement The authors thank Dr. Gisela Schott for providing data from the spontaneous reporting system of the BfArm/AkdÄ, Germany. Introduction
Elevated plasma triglycerides (>150 mg/dl) are considered to be a risk factor for arteriosclerosis and belong to the key symptoms of the metabolic syndrome.1,2 Higher elevations (>500 mg/dl) can be complicated by pancreatitis.1-4 While primary
2
hypertriglyceridemia (HTG) is largely based upon heredity, secondary (acquired) HTG is related to
hypothyroidism, older age, obesity, diabetes mellitus, chronic
kidney disease and overproduction of triglycerides in the liver, such as suggested in nonalcoholic fatty liver disease (NAFLD).2,5,6. Most frequently it comes from fat-laden diet, overuse of alcohol or pharmacotherapy, such as treatment with estrogens, glucocorticoids, β-blockers or antipsychotics.1,2,5,7 With the exception of aripiprazole8-10nearly all
antipsychotic drugs have been
associated with elevated plasma triglycerides in schizophrenic patients (Table),7-19 a population which itself is prone to develop a metabolic syndrome.20 For ziprasidone, however, the results are inconsistent.8,13 Asenapine was not associated with a meaningful change in triglycerides in 17 trials.21. For iloperidone and lurasidone the data are still too sparse to comprehensively evaluate the metabolic safety of these newly approved second generation antipsychotics.19 One small prospective clinical observational study found triglyceride elevations with tricyclics.22 There are only a few single cases reporting from elevated triglycerides secondary to serotonergic antidepressants, such as citalopram,23 fluoxetine23,24 and venlafaxine.4,24 Mirtazapine has been associated with large
increase in serum
triglycerides which induced an acute pancreatitis complicated by a life-threatening diabetic ketoacidosis in a 44-year-old woman with a history of major depression and obsessive-compulsive disorder.3 Lithium was not associated with HTG22 and small to moderate alcohol intake indeed decreased levels of plasma triglycerides25 whereas higher alcohol consumption increased these.1 Anticonvulsants gabapentinoids
26
are
not
usually
associated
with
HTG.7
However,
the
gabapentin and pregabalin have had multiple and scattered reports
through spontaneous reporting and early warning systems, such as the databases of the `Food and Drug Administration´ (FDA, USA) and the `Bundesinstitut für Arzneimittel und Medizinprodukte´ (BfArm, Germany) and `Arzneimittelkommission der deutschen Ärzteschaft´ (AkdÄ, Germany).27-29 The internet platform `eHealthMe´, which analyzed data from the FDA and social media, reported 468 (1.38%) elevated triglyceride levels in 34020 people who had reported adverse reactions when taking gabapentin.27 Furthermore, ten (0.46%) plasma triglyceride elevations were mentioned in 1160 adverse reactions related to pregabalin up today.28 The
3
BfArm/AkdÄ was aware of two (0.31%) triglyceride elevations along with gabapentin and one (0,05%) along with pregabalin out of 1822 adverse reaction reports on pregabalin and 639 on gabapentin,29 which hints at HTG to be a rather rare complication in the treatment with gabapentinoids. The confounding factors, such as comorbidity, diet or alcohol consumption, however, remained unclear in this therefore less conclusive reports.27-29 To our knowledge, the following report is the first one in peer reviewed literature that shows a significant increase of serum triglycerides in the controlled treatment with gabapentinoids, here in the case of pregabalin. Case presentation A non-smoking, somewhat obese 45-year-old Caucasian male (BMI: 28.1, waist circumference: 105 cm) with a 10 year history of oxycodone therapy for seronegative rheumatoid arthritis was admitted for fractionated opioid detoxification (stepwise taper) in the context of escalating self-dosing to a daily maximum of 240 mg Due to post-herpetic neuralgia, he has been treated by his general practitioner with daily 25 mg pregabalin26 for one week. Physical examination revealed recovered skin rash with slight cutaneous scarring in the right lower thoracic dermatomes after having shingles there approximately up to two weeks before. This skin area was very sensitive to temperature changes and touch. For three weeks he had suffered from a coming and going of moderate to severe burning and stabbing pain there which did not allow him to turn around in bed. The remaining physical und neurological examination was normal except of a condition after gallbladder removal. Mentally, the patient was sleepy and concentrated on his thoracic pain. At admission, laboratory results, including fasting glucose, fasting triglycerides, fasting total cholesterol, Creactive protein, thyroid-stimulating-hormone, lipase, alkaline phosphatase, creatinine kinase, hematological, renal and liver parameters were completely normal as well as the ECG und EEG. In the first step, pregabalin was titrated within one week to daily 600 mg which improved the neuralgia by about 80%. Thereafter, oxycodone was gradually tapered to 50% of its initial dose. In our ward routine laboratory checks were performed 14 days after the initiation or modification of psychopharmacotherapeutic drugs. Surprisingly, this lab revealed a significant sole fasting hypertriglyceridemia of 452
4
mg/dl (Figure), while the other results including lipase, fasting glucose, thyroidstimulating-hormone and total cholesterol continued to be normal. First of all we supposed changes in diet to be responsible for the HTG. However, the patient denied an increased appetite or relevant changes in his diet during the pregabalin treatment. He also denied to take or to have discontinued other medications or supplements, such as omega fatty acids. We decided to control triglycerides and to wait with lipid lowering procedures. An abdominal ultrasonography revealed an increased liver echogenicity which is typical for a fatty liver. In a detailed interview focusing on alcohol consumption no further evidence for an alcohol use disorder could be found. Therefore, the fatty liver, which could represent a preliminary state of a metabolic syndrome,20 was suggested to be of non-alcoholic origin (NAFLD)2,6 and to result from obesity6,20 of the patient. When first opiate withdrawal symptoms occurred pregabalin was directly switched to gabapentin because of good experiences even with higher doses of gabapentin in the treatment of opiate withdrawal syndrome in our hands. This switch was done after the knowledge of the elevated triglycerides and at a time when we did not attribute the HTG to pregabalin. With daily 3200 mg gabapentin both neuralgia and opiate withdrawal syndrome were under improved control than with 600 mg/day pregabalin before. Thereafter, also surprisingly, the elevated plasma triglyceride levels returned to normal within five weeks. Additionally to that time measured low-density lipoprotein (LDL: 137 mg/dl, standard value: 35 mg/dl) were unremarkable. With the exception of a mild dizziness along with the titration of pregabalin no further typical adverse reactions of gabapentinoids, such as edema or somnolence26 occurred, which would have restricted the physical activity of the patient who showed no weight gain during the treatment. Causality assessment with `Naranjo Probability Scale´30 HTG appeared after pregabalin was administered (2 points). HTG improved when pregabalin was discontinued (1 point). Plasma triglyceride level increased when the dose of pregabalin was increased (1 point). The remaining 6 questions were answered with `no´ (0 points) or `do not know´ (0 points),
5
Discussion HTG is actually not mentioned in the package insert of pregabalin (Lyrica®) and seemed to be a fairly rare complication of pregabalin therapy. According to the `Naranjo Probability Scale´30 this case report achieved at least 4 points which indicates the HTG to be a possible adverse drug reaction of pregabalin.30 Alternatively, HTG could be considered as a result from oxycodone taper or distress along with an opiate-withdrawal syndrome instead of being a consequence of a pregabalin therapy. Both these speculations, however, are pretty unlikely because conclusive reports exist neither for HTG under opiates (or during its detoxification) nor for HTG due to distress, which would be independent from alterations in lifestyle, such as changes in food intake or physical activity, that influence plasma triglyceride levels.2,5,,7,25 In support, a case-control study observed higher levels of glucose and triglycerides in opiate addicts, which were attributed to lifestyle factors.31 In the present case, previous determinations showed normal triglyceride-levels under oxycodone (Table 1) and there was no evidence for an intermittent fatty diet of the patient during the controlled inpatient treatment. Because of his obesity and fatty liver, the patient was at special risk to develop a metabolic syndrome.6,20 These circumstances might have promoted the occurrence of HTG under pregabalin. Similarly, a contribution of metabolic risk factors in the development of HTG with antipsychotics is strongly suggested.7,11,15,20,32 Because gabapentinoids are very water-soluble,26 an enrichment of pregabalin in triglyceride-rich very-low-density lipoprotein (VLDL) as found for hydrophobic antipsychotic clozapine33 is rather unlikely. Variations of genes, critically involved in the triglyceride transport and metabolism, such as apo C-III and apo AV gene (found with alcohol-associated HTG)1 or Acetyl-coenzyme A carboxylase α gene (found with antipsychotics-associated HTG),34 the rate-limiting enzyme in the synthesis of longchain fatty acids, might explain the individual reaction of drugs on plasma triglycerides. Further insight exists in the mechanisms of alcohol-associated HTG, which is related to an increased secretion of triglyceride-rich very-low-density lipoprotein (VLDL), impaired lipolysis and increased free fatty acid stream from adipose tissue to the liver.1 Recently, the antipsychotics haloperidol,clozapine, ziprasidone and risperidone were demonstrated to inhibit intracellular cholesterol synthesis in different cell lines which may be relevant in the development of HTG.32
6
Pregabalin and gabapentin are very closely related in its pharmacodynamics.26 Therefore, some authors combine both into the subgroup of `gabapentinoides´.26 In this regard the decline in HTG after switching from pregabalin to gabapentin is most interesting, especially when taking into account the number of self-reported incidences of gabapentin-associated HTGs in spontaneous reporting systems.27,29 One might speculate on a general tolerance-effect of gabapentinoids to HTG in the presented case. Re-challenge of pregabalin was not performed, in order not to jeopardize the clinical improvement with gabapentin. A pharmacokinetic basis of the HTG is unlikely because neither pregabalin nor gabapentin binds to plasma proteins and is metabolized by or inhibits hepatic enzymes.26 Nonetheless, there are some pharmacologic differences that should be considered in the discussion why pregabalin may have caused HTG and not the closely related gabapentin. Firstly, gabapentin is more slowly absorbed and has a lower bioavailability (33-66% vs. >90%).26 Secondly and more importantly, gabapentin plasma concentrations have been found to have a non-linear relationship to increasing oral doses.26 In the case of pregabalin plasma concentrations increase linearly with increasing dose.26 Thirdly, pregabalin has a greater inhibitory effect on voltage-gated calcium channels containing the alpha2-delta-1 subunits.26 However, a link between these calcium channels and lipid transport, synthesis or metabolism could not be found in literature. Further studies are needed to support the assumption of a closer association between gabapentinoid therapy and HTG. Disclosure Udo Bonnet, MD, Behnaz Taazimi, MD and Heinz-Dieter Grabbe, MD are affiliated with the Department of Psychiatry, Psychotherapy and Psychosomatics of the Lutherian Hospital of Castrop-Rauxel, Germany. The authors report no proprietary or commercial interests in any product mentioned or concept discussed in this article. Acknowledgement The authors thank Gisela Schott, MD for providing data from the spontaneous reporting system of the BfArm/AkdÄ, Germany.
7
Table: `Top ten´ of psychopharmaca associated with HTG Drug
Odds of occurrence (+ to +++)
Severity (+ to +++)**
Clozapine 2,6,8,15
++
+++
Olanzapine 8,10,11,14,17
++
++
Quetiapine 8,11,13,16,18
+
+++
Haloperidol and FGA* 2,6,15,32
+
+
Risperidone 8,12,32
+
+
Paliperidone 9,19
+
+
Venlafaxine 4,24
+
+++
Mirtazapine 3
+
+++
Tricyclics 22
+
+
SSRI 23,24
+
+
*First generation antipsychotics **evaluation: >+ if complications of HTG, such as pancreatitis or xanthomas have been described, >++ if HTG-associated life-threatening conditions or fatalities have been described
8
plasma triglyceride concentrations
mg/dl 500 450 400 350 300 250 200 150 100 50
time th th th th th th th th 10 th 10 th 02 15 21 04 07 02 19 31 Feb 2011 June 2011 Oct 2013 Nov 2013 Dec 2013 Jan 2014 pregabalin 240 mg
3200 mg gabapentin 2400 mg
200mg 120 mg oxycodone
Figure: Course of the fasting hypertriglyceridemia during outpatient (dashed line) and inpatient treatment (solid line). Pregabalin was titrated from 25 mg to 600 mg daily from 02th to 15th October. Daily doses of gabapentin and oxycodone were shown in the boxes. Standard value of triglycerides:
Pregabalin-relatedhypertriglyceridemia Udo Bonnet MD, Behnaz Taazimi MD, HeinzDieter Grabbe MD
PII: DOI: Reference:
S0033-3182(14)00056-5 http://dx.doi.org/10.1016/j.psym.2014.03.009 PSYM456
To appear in:
Psychosomatics
Cite this article as: Udo Bonnet MD, Behnaz Taazimi MD, Heinz-Dieter Grabbe MD, Pregabalin-relatedhypertriglyceridemia, Psychosomatics, http://dx.doi.org/ 10.1016/j.psym.2014.03.009 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Pregabalin-related hypertriglyceridemia
Udo Bonnet, MD1, Behnaz Taazimi, MD1, Heinz-Dieter Grabbe1, MD 1
Department of Psychiatry, Psychotherapy and Psychosomatics, Evangelisches
Krankenhaus Castrop-Rauxel, Academic Teaching Hospital of the University of Duisburg/Essen, Germany Key words pregabalin, gabapentin, elevated triglycerides, metabolic syndrome
Corresponding author Prof. Dr. med. Udo Bonnet Klinik für Psychiatrie, Psychotherapie und Psychosomatik Evangelisches Krankenhaus Castrop-Rauxel Grutholzallee 21 44577 Castrop-Rauxel Germany Telephone number: (+49) 02305/1022858 Fax number: (+49) 02305/1022860 Email: [email protected]
Acknowledgement The authors thank Dr. Gisela Schott for providing data from the spontaneous reporting system of the BfArm/AkdÄ, Germany. Introduction
Elevated plasma triglycerides (>150 mg/dl) are considered to be a risk factor for arteriosclerosis and belong to the key symptoms of the metabolic syndrome.1,2 Higher elevations (>500 mg/dl) can be complicated by pancreatitis.1-4 While primary
2
hypertriglyceridemia (HTG) is largely based upon heredity, secondary (acquired) HTG is related to
hypothyroidism, older age, obesity, diabetes mellitus, chronic
kidney disease and overproduction of triglycerides in the liver, such as suggested in nonalcoholic fatty liver disease (NAFLD).2,5,6. Most frequently it comes from fat-laden diet, overuse of alcohol or pharmacotherapy, such as treatment with estrogens, glucocorticoids, β-blockers or antipsychotics.1,2,5,7 With the exception of aripiprazole8-10nearly all
antipsychotic drugs have been
associated with elevated plasma triglycerides in schizophrenic patients (Table),7-19 a population which itself is prone to develop a metabolic syndrome.20 For ziprasidone, however, the results are inconsistent.8,13 Asenapine was not associated with a meaningful change in triglycerides in 17 trials.21. For iloperidone and lurasidone the data are still too sparse to comprehensively evaluate the metabolic safety of these newly approved second generation antipsychotics.19 One small prospective clinical observational study found triglyceride elevations with tricyclics.22 There are only a few single cases reporting from elevated triglycerides secondary to serotonergic antidepressants, such as citalopram,23 fluoxetine23,24 and venlafaxine.4,24 Mirtazapine has been associated with large
increase in serum
triglycerides which induced an acute pancreatitis complicated by a life-threatening diabetic ketoacidosis in a 44-year-old woman with a history of major depression and obsessive-compulsive disorder.3 Lithium was not associated with HTG22 and small to moderate alcohol intake indeed decreased levels of plasma triglycerides25 whereas higher alcohol consumption increased these.1 Anticonvulsants gabapentinoids
26
are
not
usually
associated
with
HTG.7
However,
the
gabapentin and pregabalin have had multiple and scattered reports
through spontaneous reporting and early warning systems, such as the databases of the `Food and Drug Administration´ (FDA, USA) and the `Bundesinstitut für Arzneimittel und Medizinprodukte´ (BfArm, Germany) and `Arzneimittelkommission der deutschen Ärzteschaft´ (AkdÄ, Germany).27-29 The internet platform `eHealthMe´, which analyzed data from the FDA and social media, reported 468 (1.38%) elevated triglyceride levels in 34020 people who had reported adverse reactions when taking gabapentin.27 Furthermore, ten (0.46%) plasma triglyceride elevations were mentioned in 1160 adverse reactions related to pregabalin up today.28 The
3
BfArm/AkdÄ was aware of two (0.31%) triglyceride elevations along with gabapentin and one (0,05%) along with pregabalin out of 1822 adverse reaction reports on pregabalin and 639 on gabapentin,29 which hints at HTG to be a rather rare complication in the treatment with gabapentinoids. The confounding factors, such as comorbidity, diet or alcohol consumption, however, remained unclear in this therefore less conclusive reports.27-29 To our knowledge, the following report is the first one in peer reviewed literature that shows a significant increase of serum triglycerides in the controlled treatment with gabapentinoids, here in the case of pregabalin. Case presentation A non-smoking, somewhat obese 45-year-old Caucasian male (BMI: 28.1, waist circumference: 105 cm) with a 10 year history of oxycodone therapy for seronegative rheumatoid arthritis was admitted for fractionated opioid detoxification (stepwise taper) in the context of escalating self-dosing to a daily maximum of 240 mg Due to post-herpetic neuralgia, he has been treated by his general practitioner with daily 25 mg pregabalin26 for one week. Physical examination revealed recovered skin rash with slight cutaneous scarring in the right lower thoracic dermatomes after having shingles there approximately up to two weeks before. This skin area was very sensitive to temperature changes and touch. For three weeks he had suffered from a coming and going of moderate to severe burning and stabbing pain there which did not allow him to turn around in bed. The remaining physical und neurological examination was normal except of a condition after gallbladder removal. Mentally, the patient was sleepy and concentrated on his thoracic pain. At admission, laboratory results, including fasting glucose, fasting triglycerides, fasting total cholesterol, Creactive protein, thyroid-stimulating-hormone, lipase, alkaline phosphatase, creatinine kinase, hematological, renal and liver parameters were completely normal as well as the ECG und EEG. In the first step, pregabalin was titrated within one week to daily 600 mg which improved the neuralgia by about 80%. Thereafter, oxycodone was gradually tapered to 50% of its initial dose. In our ward routine laboratory checks were performed 14 days after the initiation or modification of psychopharmacotherapeutic drugs. Surprisingly, this lab revealed a significant sole fasting hypertriglyceridemia of 452
4
mg/dl (Figure), while the other results including lipase, fasting glucose, thyroidstimulating-hormone and total cholesterol continued to be normal. First of all we supposed changes in diet to be responsible for the HTG. However, the patient denied an increased appetite or relevant changes in his diet during the pregabalin treatment. He also denied to take or to have discontinued other medications or supplements, such as omega fatty acids. We decided to control triglycerides and to wait with lipid lowering procedures. An abdominal ultrasonography revealed an increased liver echogenicity which is typical for a fatty liver. In a detailed interview focusing on alcohol consumption no further evidence for an alcohol use disorder could be found. Therefore, the fatty liver, which could represent a preliminary state of a metabolic syndrome,20 was suggested to be of non-alcoholic origin (NAFLD)2,6 and to result from obesity6,20 of the patient. When first opiate withdrawal symptoms occurred pregabalin was directly switched to gabapentin because of good experiences even with higher doses of gabapentin in the treatment of opiate withdrawal syndrome in our hands. This switch was done after the knowledge of the elevated triglycerides and at a time when we did not attribute the HTG to pregabalin. With daily 3200 mg gabapentin both neuralgia and opiate withdrawal syndrome were under improved control than with 600 mg/day pregabalin before. Thereafter, also surprisingly, the elevated plasma triglyceride levels returned to normal within five weeks. Additionally to that time measured low-density lipoprotein (LDL: 137 mg/dl, standard value: 35 mg/dl) were unremarkable. With the exception of a mild dizziness along with the titration of pregabalin no further typical adverse reactions of gabapentinoids, such as edema or somnolence26 occurred, which would have restricted the physical activity of the patient who showed no weight gain during the treatment. Causality assessment with `Naranjo Probability Scale´30 HTG appeared after pregabalin was administered (2 points). HTG improved when pregabalin was discontinued (1 point). Plasma triglyceride level increased when the dose of pregabalin was increased (1 point). The remaining 6 questions were answered with `no´ (0 points) or `do not know´ (0 points),
5
Discussion HTG is actually not mentioned in the package insert of pregabalin (Lyrica®) and seemed to be a fairly rare complication of pregabalin therapy. According to the `Naranjo Probability Scale´30 this case report achieved at least 4 points which indicates the HTG to be a possible adverse drug reaction of pregabalin.30 Alternatively, HTG could be considered as a result from oxycodone taper or distress along with an opiate-withdrawal syndrome instead of being a consequence of a pregabalin therapy. Both these speculations, however, are pretty unlikely because conclusive reports exist neither for HTG under opiates (or during its detoxification) nor for HTG due to distress, which would be independent from alterations in lifestyle, such as changes in food intake or physical activity, that influence plasma triglyceride levels.2,5,,7,25 In support, a case-control study observed higher levels of glucose and triglycerides in opiate addicts, which were attributed to lifestyle factors.31 In the present case, previous determinations showed normal triglyceride-levels under oxycodone (Table 1) and there was no evidence for an intermittent fatty diet of the patient during the controlled inpatient treatment. Because of his obesity and fatty liver, the patient was at special risk to develop a metabolic syndrome.6,20 These circumstances might have promoted the occurrence of HTG under pregabalin. Similarly, a contribution of metabolic risk factors in the development of HTG with antipsychotics is strongly suggested.7,11,15,20,32 Because gabapentinoids are very water-soluble,26 an enrichment of pregabalin in triglyceride-rich very-low-density lipoprotein (VLDL) as found for hydrophobic antipsychotic clozapine33 is rather unlikely. Variations of genes, critically involved in the triglyceride transport and metabolism, such as apo C-III and apo AV gene (found with alcohol-associated HTG)1 or Acetyl-coenzyme A carboxylase α gene (found with antipsychotics-associated HTG),34 the rate-limiting enzyme in the synthesis of longchain fatty acids, might explain the individual reaction of drugs on plasma triglycerides. Further insight exists in the mechanisms of alcohol-associated HTG, which is related to an increased secretion of triglyceride-rich very-low-density lipoprotein (VLDL), impaired lipolysis and increased free fatty acid stream from adipose tissue to the liver.1 Recently, the antipsychotics haloperidol,clozapine, ziprasidone and risperidone were demonstrated to inhibit intracellular cholesterol synthesis in different cell lines which may be relevant in the development of HTG.32
6
Pregabalin and gabapentin are very closely related in its pharmacodynamics.26 Therefore, some authors combine both into the subgroup of `gabapentinoides´.26 In this regard the decline in HTG after switching from pregabalin to gabapentin is most interesting, especially when taking into account the number of self-reported incidences of gabapentin-associated HTGs in spontaneous reporting systems.27,29 One might speculate on a general tolerance-effect of gabapentinoids to HTG in the presented case. Re-challenge of pregabalin was not performed, in order not to jeopardize the clinical improvement with gabapentin. A pharmacokinetic basis of the HTG is unlikely because neither pregabalin nor gabapentin binds to plasma proteins and is metabolized by or inhibits hepatic enzymes.26 Nonetheless, there are some pharmacologic differences that should be considered in the discussion why pregabalin may have caused HTG and not the closely related gabapentin. Firstly, gabapentin is more slowly absorbed and has a lower bioavailability (33-66% vs. >90%).26 Secondly and more importantly, gabapentin plasma concentrations have been found to have a non-linear relationship to increasing oral doses.26 In the case of pregabalin plasma concentrations increase linearly with increasing dose.26 Thirdly, pregabalin has a greater inhibitory effect on voltage-gated calcium channels containing the alpha2-delta-1 subunits.26 However, a link between these calcium channels and lipid transport, synthesis or metabolism could not be found in literature. Further studies are needed to support the assumption of a closer association between gabapentinoid therapy and HTG. Disclosure Udo Bonnet, MD, Behnaz Taazimi, MD and Heinz-Dieter Grabbe, MD are affiliated with the Department of Psychiatry, Psychotherapy and Psychosomatics of the Lutherian Hospital of Castrop-Rauxel, Germany. The authors report no proprietary or commercial interests in any product mentioned or concept discussed in this article. Acknowledgement The authors thank Gisela Schott, MD for providing data from the spontaneous reporting system of the BfArm/AkdÄ, Germany.
7
Table: `Top ten´ of psychopharmaca associated with HTG Drug
Odds of occurrence (+ to +++)
Severity (+ to +++)**
Clozapine 2,6,8,15
++
+++
Olanzapine 8,10,11,14,17
++
++
Quetiapine 8,11,13,16,18
+
+++
Haloperidol and FGA* 2,6,15,32
+
+
Risperidone 8,12,32
+
+
Paliperidone 9,19
+
+
Venlafaxine 4,24
+
+++
Mirtazapine 3
+
+++
Tricyclics 22
+
+
SSRI 23,24
+
+
*First generation antipsychotics **evaluation: >+ if complications of HTG, such as pancreatitis or xanthomas have been described, >++ if HTG-associated life-threatening conditions or fatalities have been described
8
plasma triglyceride concentrations
mg/dl 500 450 400 350 300 250 200 150 100 50
time th th th th th th th th 10 th 10 th 02 15 21 04 07 02 19 31 Feb 2011 June 2011 Oct 2013 Nov 2013 Dec 2013 Jan 2014 pregabalin 240 mg
3200 mg gabapentin 2400 mg
200mg 120 mg oxycodone
Figure: Course of the fasting hypertriglyceridemia during outpatient (dashed line) and inpatient treatment (solid line). Pregabalin was titrated from 25 mg to 600 mg daily from 02th to 15th October. Daily doses of gabapentin and oxycodone were shown in the boxes. Standard value of triglycerides:
