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NI FEATURE: FACING ADVERSITY…TOMORROW IS ANOTHER DAY! - LETTERS TO EDITOR
Year : 2019  |  Volume : 67  |  Issue : 3  |  Page : 858-861

Acute confusional state induced by diclofenac: Report and review of literature


Department of Neurology, Ramaiah Medical College, Bengaluru, Karnataka, India

Date of Web Publication23-Jul-2019

Correspondence Address:
Dr. Mahendra Javali
Department of Neurology, Ramaiah Medical College and Hospitals, Bengaluru - 560 054, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.263243

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How to cite this article:
Gupta D, Javali M, Pradeep R, Mehta A, Acharya PT, Srinivasa R. Acute confusional state induced by diclofenac: Report and review of literature. Neurol India 2019;67:858-61

How to cite this URL:
Gupta D, Javali M, Pradeep R, Mehta A, Acharya PT, Srinivasa R. Acute confusional state induced by diclofenac: Report and review of literature. Neurol India [serial online] 2019 [cited 2019 Aug 24];67:858-61. Available from: http://www.neurologyindia.com/text.asp?2019/67/3/858/263243




Sir,

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used over-the-counter and prescription drugs for the management of pain and inflammation. They account for 5–10% of all drug prescriptions.[1] Diclofenac is a potent NSAID, available in topical, oral, rectal, and intramuscular formulations, making it one of the preferable choices in inflammatory rheumatic and nonrheumatic diseases. The efficacy of diclofenac is relatively well known. The safety and adverse risk profiles have been reviewed recently by both European as well as Australian Pharmacovigilance Committees [2] The most common adverse effects include gastrointestinal, renal, and cardiac events. Recent reports have mentioned some rare but clinically relevant events such as psychiatric disturbances,[3] tissue necrosis [4] and rhabdomyolysis [5] associated with this drug. We report two patients who developed an acute-onset, self-resolving confusional state after the use of diclofenac.

The first patient was a 64-year old lady, without any previous comorbidities, who underwent laparoscopic umbilical mesh hernioplasty for paraumbilical hernia. Postoperatively, on day 2, she was given diclofenac transdermal patch for pain. On postoperative day 3, she developed agitation and altered sensorium with a drop in Glasgow Coma Scale (GCS) score, for which she had to be intubated and maintained on ventilator. She was afebrile. The metabolic workup with total counts, electrolytes, kidney and liver function, blood and urine cultures, chest radiograph, and brain imaging were all normal. A lumbar puncture showed normal cerebrospinal fluid (CSF) analysis. Electroencephalogram (EEG) showed slowing of background rhythm [Figure 1]. The diclofenac patch was removed and the patient showed symptomatic improvement within 8–10 h. She was extubated and did not have any residual deficits. A repeat EEG was normal. Consequently, her symptoms were attributed to the diclofenac patch.
Figure 1: EEG showing diffuse slowing of background rhythm

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The second patient was a 52-year old lady, without previous comorbidities, who experienced knee pain after her daily morning walk. She took two tablets of diclofenac 50 mg. Around 2 h after taking diclofenac, the relatives noticed that she became agitated, confused, and was not following commands. On presentation to the hospital, she was in delirium. She was afebrile; there was no neck rigidity. Neurological examination did not reveal any lateralizing deficits. Blood investigations, total counts, electrolytes, renal and liver function tests, brain imaging, and CSF analysis were normal. EEG at presentation could not be done as the patient was agitated. She was managed with intravenous hydration and symptomatic therapy, after which she recovered within 10–12 h, without any residual deficits. EEG done on the day after admission was normal.

Diclofenac is a nonselective cyclooxygenase (COX) inhibitor with analgesic, anti-inflammatory, and antipyretic properties. In addition, novel mechanisms including stimulation of nitric oxide-cyclic guanosine monophosphate (NO–cGMP) pathway,[6] N-methyl-D-aspartate (NMDA)-receptor inhibition,[7] inhibition of peroxisome proliferator-activated receptor gamma (PPAR)-γ[8] and effects on various cytokines and thromboxane A2 receptors have been proposed. Psychiatric side effects are emerging with the use of NSAIDs, more with the newer selective COX-2 than the older nonselective ones. The most common psychiatric symptoms reported are disorientation,[9] restlessness, agitation,[10] psychosis, personality changes, anxiety, and depression [Table 1].[9],[10],[11] In the last 20 years, of all the diclofenac-related side effects reported to the United States Food and Drug administration, less than 0.5% patients reported psychiatric manifestations. Delirium was more common in females above 60 years of age, who had been taking diclofenac for less than 1 month or were taking furosemide along with diclofenac.[12] The underlying mechanisms are still debatable and various theories have been proposed [Table 2].[13],[14],[15],[16],[17],[18],[19] Prostanoids and prostaglandin modulation of PPAR-γ receptors have been suggested to play a role in the pathogenesis of neuropsychiatric syndromes such as depression, schizophrenia, and probably delirium.[8],[13] New research on the mechanism of diclofenac points to a more selective COX-2 inhibition, similar to celecoxib, which may modulate the central nervous system (CNS) side effects.[17] COX-2 is the most abundant CNS isoform and is involved in synaptic transmission. Sparse case reports regarding psychiatric side-effects of NSAIDs make it difficult to define the risk factors, diagnostic criteria, and their management, and we believe our report would add to the growing body of literature on the subject.
Table 1: Previously reported cases of diclofenac-associated delirium

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Table 2: Proposed mechanisms for diclofenac-associated delirium

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Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Jones R. Nonsteroidal anti-inflammatory drug prescribing: Past, present, and future. Am J Med 2001;10:S4-7.  Back to cited text no. 1
    
2.
Department of Health. Safety review of Diclofenac. Therapeutic Goods Administration. Available from: https://www.tga.gov.au/safety-review-diclofenac [Last accessed on 2018 Mar 01].  Back to cited text no. 2
    
3.
Onder G, Pellicciotti F, Gambassi C, Bernabei R. NSAID-related psychiatric adverse events. Who is at Risk? Drugs 2004;64:2619-27.  Back to cited text no. 3
    
4.
Giovannetti M, Machado MA, Borrelli Júnior M, Ikejiri CI, Alonso N, Branco PD. Tissue necrosis: A side effect of sodium diclofenac: Report of cases and discussion of the physiopathology. Rev Hosp Clin Fac Med Sao Paulo 1993;48:39-42.  Back to cited text no. 4
    
5.
Delrio, FG, Park Y, Herzlich B, Grob D. Diclofenac-induced Rhabdomyolysis. Am J Med Sci 1996;312:95-9.  Back to cited text no. 5
    
6.
Tonussi CR, Ferreira SH. Mechanism of diclofenac analgesia: Direct blockade of inflammatory sensitization. Eur J Pharmacol 1994;251:173-9.  Back to cited text no. 6
    
7.
Dong X-D, Svensson P, Cairns BE. The analgesic action of topical diclofenac may be mediated through peripheral NMDA receptor antagonism. Pain 2009;147:36-45.  Back to cited text no. 7
    
8.
Adamson DJA, Frew D, Tatoud R, Wolf CR, Palmer CNA. Diclofenac antagonizes peroxisome proliferator-activated receptor-γ signaling. Mol Pharmacol 2012;61:7-12.  Back to cited text no. 8
    
9.
Okumura A, Fukumoto Y, Hayakawa F, Nakano T, Higuchi K, Kamiya H, et al. Antipyretics and delirious behavior during febrile illness. Pediatr Int 2006;48:40-3.  Back to cited text no. 9
    
10.
Jain R, Agarwal A, Navjeet K. Delirium in immediate postoperative period in a patient operated for laparoscopic cholecystectomy: A case report. J Anesth Crit Care Open Access 2017;8:00314.  Back to cited text no. 10
    
11.
Faaij RA, Ziere G, Zietse R, Van der Cammen TJ. Delirium due to a drug-drug interaction of lithium and an NSAID. J Nutr Health Aging 2009;13:275-6.  Back to cited text no. 11
    
12.
eHealthMe. Diclofenac sodium and Delirium - from FDA reports. Available from: https://www.ehealthme.com/ds/diclofenac-sodium/delirium/. [Last accessed on 2018 Sep 26].  Back to cited text no. 12
    
13.
García-Bueno B, Pérez-Nievas BG, Leza JC. Is there a role for the nuclear receptor PPAR-γ in neuropsychiatric diseases? Int J Neuropsychopharmacol 2010;13:1411-29.  Back to cited text no. 13
    
14.
Edwards SR, Mather LE, Lin Y, Power I, Cousins MJ. Glutamate and kynurenate in the rat central nervous system following treatments with tail ischaemia or diclofenac. J Pharm Pharmacol 2000;52:59-66.  Back to cited text no. 14
    
15.
Lakhan SE, Caro M, Hadzimichalis N. NMDA receptor activity in neuropsychiatric disorders. Front Psychiatry 2013;4:52.  Back to cited text no. 15
    
16.
Kakita H, Aoyama M, Nagaya Y, Asai H, Hussein MH, Suzuki M, et al. Diclofenac enhances proinflammatory cytokine-induced phagocytosis of cultured microglia via nitric oxide production. Toxicol Appl Pharmacol 2013;268:99-105.  Back to cited text no. 16
    
17.
Altman R, Bosch B, Brune K, Patrignani P, Young C. Advances in NSAID development: Evolution of diclofenac products using pharmaceutical technology. Drugs 2015;75:859-77.  Back to cited text no. 17
    
18.
MacKnight C, Rojas-Fernandez CH. Celecoxib- and rofecoxib-induced delirium. J Neuropsychiatry Clin Neurosci 2001;13:305-6.  Back to cited text no. 18
    
19.
Muralee S, Bober D, Tampi R. Delirium from the COX-2 inhibitor refecoxib. Psychosomatics 2004;45:361-3.  Back to cited text no. 19
    


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