Ibuprofen Dependence: A Case Report F. Etcheverrigaray1*, M. Grall-Bronnec2, 3*, M.-C. Blanchet2, P. Jolliet1, 3, C. Victorri-Vigneau1, 3 1

Center for Evaluation and Information on Pharmacodependence, Clinical Pharmacology Department, University Hospital, Nantes, France 2 Addictology and Psychiatry Department, University Hospital, Nantes, France 3 EA 4275, Biostatistics, Pharmacoepidemiology and Subjective Measures in Health Sciences, Nantes University, Nantes, France

Abstract



Ibuprofen is currently widely prescribed and has not been reported to produce dependence. We report the case of a 17-year old patient who presented many positive psychics symptoms related to a pharmacological dependence. During the treatment, she adjusted herself posology as she developed withdrawal symptoms. Pharmacological evidences (effect on COX-1 and COX-2, FAAH and PPARs) allow us to formulate hypotheses explaining this effect.

Key words ibuprofen · dependence · cannabinoid receptor modulators · peroxisome proliferator-activated

Introduction



Ibuprofen is a member of the non-steroidal anti-inflammatory drug family (NSAIDs), which is a group of medications widely prescribed for its analgesic, anti-inflammatory and antipyretic effects. To the best of our knowledge, it has not been reported to induce addiction. Hereafter we report the case of a teenager who presented several symptoms of dependence occurred when she was treated by this drug.

Case Report



The patient was a 17-year-old girl, with no specific medical history except for nicotine dependence and a major depressive episode of mild intensity which prompted her to consult a psychiatrist in January 2013. He prescribed her mirtazapine (15 mg/day) in March 2013, which significantly helped improve her mood and reduced her state of anxiety. Her father had a history of dependence to alcohol. For many months now, she had been suffering from knee chondropathy. Ibuprofen was introduced in February 2013 to manage her pain, since acetaminophen was ineffective. The initial dose was 400 mg 4 times a day, according to the doses mentioned in the approval of the drug. However, pain was not entirely relieved with this treatment [visual analogue scale (VAS): 5/10]. Conse* These two authors are first co-authors.

quently, she progressively increased the dosage on her own initiative, from 400 mg 4 times a day to 400 mg 8 times a day 3 months later, in April 2013, without this increase having any effect on her pain. She then abruptly stopped taking ibuprofen, which led to the onset of withdrawal signs (tremors, sweating, anxiety). These symptoms were non-specific; the school nurse, who knew the girl well, was the one who noted the symptoms. Other more ordinary causes, especially at this age, such as hypoglycemic fits or panic attacks, were discarded. The school nurse then alerted her mother and her psychiatrist. The girl was sent to an addictology department to be evaluated. In the meantime, the girl started taking ibuprofen again against the advice of her psychiatrist, and then gradually started reducing the doses, until she stopped taking it completely. Her mother made this gradual withdrawal possible, by controlling the doses taken. The girl remained sober for 3 weeks. At the first visit in the specialised department in June 2013, the girl resumed her consumption of ibuprofen (400 mg 4–5 times a day), in spite of the school nurse and the psychiatrist’s warnings. She explained it by her fear of feeling withdrawal symptoms again, but also by the specific effects she was looking for (anxiolysis, but also stimulation), which particularly helped her face her school obligations. She specified that the anxiety and irritability she felt made it impossible for her to wait the recommended 6-h period between each take. She especially confirmed that she did not want to stop taking ibuprofen, even though it had virtually no effect on her knee pains, and even though she was fully aware of the negative consequences it caused (headaches, conflicts with her mother). In spite of her parents monitoring her, she secretly kept on taking her pills, with a feeling that she was losing control. She then agreed to limiting her consumption to 4 takes of 400 mg a day. During her second visit one month later, the girl complained that she failed at remaining under the 1 600 mg/day limit, and declared taking the medicine each time she needed to feel more relaxed. On her 3rd and last visit, she had been trying again to stop her consumption for 2 weeks, after her friends shared their concern. She then felt the same withdrawal symptoms, with added irritability and increased knee pains (VAS: 8/10). The diagnosis of ibuprofen dependence was confirmed by the addiction doctor, according to the DSM-IV [1]. Indeed, 6 criteria ▶ Table 1. Now that DSM-5 of the DSM-IV were met, as shown in ● [2] is available, severe substance use disorder can be diagnosed, for at least 6 criteria have been diagnosed insofar, as indicated ▶ Table 1. in ●

Discussion



As a preamble, we wish to underline that the patient never used ibuprofen to help with her headaches, which appeared with the treatment. This case is therefore different from the NSAID abuse cases other authors might have presented [3–5]. Ibuprofen, by inhibiting COX-1 and COX-2 enzymes, blocks prostaglandin (PG) synthesis [6–8]. As far as their effect on dependence goes, data are conflicting. Some reports show that PGs facilitate or attenuate dependence and attenuate morphineinduced withdrawal symptoms [7, 9], but others show no effect at all on reducing withdrawal symptoms following the intracerebral administration of PGF2alpha [10]. We can assume that central PGs have a role in the induction of drug dependence, either

Etcheverrigaray F et al. Ibuprofen Dependence: A Case … Pharmacopsychiatry 2014; 47: 115–117

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116 Letter

Table 1 Ibuprofen dependence according to the DSM-IV and ibuprofen use disorder according to the DSM-5. Criteria

DSM-IV

DSM-5 SUD

Comments

Dependence criteria criteria X

X

repeated attempts to quit using/control use large amount of time spent using craving Social impairment failure to fulfil major role obligations at school, etc. social/interpersonal problems related to use

X –

X – NA

activities given up to use

X

X

X

– X

continuing ibuprofen use despite the appearance of headaches

X X

X X

increased dose to achieve the desire effect tremor, sweating, anxiety, irritability when abrupt withdrawal

Risky use hazardous use physical/psychological problems related to use Pharmacological criteria tolerance withdrawal

X X

dose above those indicated in the approval and in larger amounts than attempted 3 attempts to stop using in an interval of 3 months

inability to go to school without using ibuprofen interpersonal conflicts with her mother about the ibuprofen use classes missed and large amount of time spent at the school infirmary when withdrawal symptoms occur

X: criterion met; -: criterion not met; SUD: substance use disorder; NA: not assessed

directly or by managing catecholaminergic, serotoninergic and cholinergic neurons in the CNS [11]. Ibuprofen, through its action as a COX inhibitor, may also play a role in the development of addiction in the patient. Moreover, ibuprofen has an influence on the cannabinoid system by inhibiting fatty acid amine hydrolase (FAAH) or by inhibiting a possible intracellular transporter of endocannabinoids [12]. There is evidence showing that central PGs may be connected to the endogenous cannabinoids system through an anandamide [13] (a central and peripheral CB-1 agonist) [14] such as delta-9tetrahydrocannabinol (THC). Mediated by its inhibition of FAAH or endocannabinoid intracellular transporter, ibuprofen enhances the levels of anandamide in the CNS, along with its effects [15]. As FAAH inhibition helps attenuate opioid withdrawal signs in mice [16], it may also prevent withdrawal symptoms caused by other substances from developing. Moreover, it has been demonstrated that anandamide increases dopamine levels in the nucleus accumbens (NA), thus participating in signalling the brain’s reward process [17]. We can imagine that ibuprofen administration, by inhibiting FAAH, increases activation of the mesolimbic dopamine system, as it does for nicotine [18]. This effect could contribute to the craving for her drug observed in the patient. Moreover, we saw that anandamide acts as a central (and peripheral) CB-1 agonist [14]. This property leads to antinociception induction by activating the noradrenergic system [19]. However, it also has an action mediated by GABA and glutamate [20]. It may be that anandamide also acts on the mesolimbic reward system by acting through these different systems. We saw that ibuprofen enhances anadamide levels in the CNS [15]. When the cannabinoid receptors are chronically stimulated, the receptor adapts through down-regulation and desensitisation [21], but we can also notice a binding decrease of agonists in CB receptors (depending on where the receptor is localised in the brain) [21]. These effects result in the development of a tolerance toward the drug [21], potentially explaining the increased doses of ibuprofen used by the patient in order to manage her pain, but also her craving for it.

Ibuprofen also acts as a peroxisome proliferator-activated α and γ receptor (PPAR) agonist at micromolar concentrations [22, 23], effective at the terminal regions in the nucleus accumbens, which is an area involved in abuse potential [24]; there lies the interest of PPARs in treating drug addiction. Indeed some studies have shown that PPAR α agonists may increase [25] or decrease [26] ethanol intake, induce sensitisation to morphine but not to cocaine [27], and decrease the acquisition of nicotine selfadministration [28]. The PPAR γ agonist can decrease alcohol intake and self-administration [29], and limits sensitisation to metamphetamines but not to antagonists [30]. Moreover, PPAR α agonists mediate their action toward addictive drugs by modulating dopamine levels in the nucleus accumbens shell [28, 31], whereas PPAR γ was identified in the ventral tegmental area, colocalised with tyrosine hydroxylase; some authors have suggested PPAR γ expression in dopamine cells [32]. These arguments are all in favour PPAR playing a role in many aspects of drug addiction. Yet, in these studies, PPAR activators or inhibitors act on another substance-related disorder, and this substance increases dopamine levels by another way of action beside the cannabinoid system. Conversely, in our case, the substance the teenager is dependent on is the PPAR activator itself, acting on dopamine levels by cannabinoid receptor agonism. Consequently, we can assume that ibuprofen modulates the dopamine reward system, but not its effect on increasing or decreasing drug consumption. We have seen that ibuprofen dependence assumptions may be explained by its action on the cannabinoid system, but also by dopamine level modulation on the nucleus accumbens via PPARs. Further investigations are needed to deepen the exact involvement of each system, which could explain more precisely the appearance of ibuprofen dependence in this teenage patient.

Conflict of Interest



The authors declare no conflict of interest.

Etcheverrigaray F et al. Ibuprofen Dependence: A Case … Pharmacopsychiatry 2014; 47: 115–117

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Impaired control used larger amounts/for a longer period of time

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Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1371868 Published online ahead of print: 24 April 2014 Pharmacopsychiatry 2014; 47: 115–117 © Georg Thieme Verlag KG Stuttgart · New York ISSN 0176-3679 Correspondence F. Etcheverrigaray Clinical Pharmacology Department Center for Evaluation and Information on Pharmacodependence 9 quai Moncousu University Hospital 44093 Nantes cedex 1 France Tel.: + 33/240/084 073 Fax: + 33/240/084 097 [email protected]

Etcheverrigaray F et al. Ibuprofen Dependence: A Case … Pharmacopsychiatry 2014; 47: 115–117

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Ibuprofen dependence: a case report.

Ibuprofen is currently widely prescribed and has not been reported to produce dependence. We report the case of a 17-year old patient who presented ma...
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