Possible Causal Link Between Idiopathic Intracranial Hypertension and the Misuse of Codeine-Based Products

To The Editor:

In recent years codeine has become available in pharmacies over-the-counter (OTC) drugs. The nonmedical use of OTC drugs has progressively emerged as a major health problem among the adolescents. In 2008, the Substance Abuse and Mental Health Services Administration released the Annual National Survey on Drug Use and Health report, which revealed that in 2006, ∼ 3,100,000 people in the United States ages 12–25 stated that they had used OTC cough and cold medicine to “get high” (Substance Abuse and Mental Health Services Administration 2008). The increase in abuse is likely furthered by the beliefs of the youth that because these medications are legal, they are safer and not addictive.

OTC codeine-based products include doses up to 20 mg of codeine per pill, combined with analgesics. It is a common belief quoted on the Internet that companies formulate codeine in combination with other active ingredients such as acetaminophen to prevent excessive use (Codeine FAQ 1996). However, recreational codeine users frequently attempt to purify codeine formulations by removing acetaminophen, aspirin, and other ingredients, thereby circumventing potential toxicity from these substances. Users of codeine also report online “cold water extraction” (CWE) processes using multifiltration of the product in order to yield the codeine base that allows removal of acetaminophen and aspirin (ADH-The Page 2005; Codeine.50g.com 2005; drugs-forum.com 2008).

Prior reports include a large number adverse effects related to the use of OTC codeine-based products, but pseudotumor cerebri (PC) has not been found in the previous data. To our knowledge, we are reporting what is likely the first case of such an association with chronic use of codeine.

Case Report

The patient was a previously healthy 17-year-old girl living with her mother and sister. Approximately 4 years earlier, her parents divorced and she never saw her father during this time. At the beginning of the previous year she became unhappy and learned a “feel-good idea” from a friend working in the tattoo studio. She thought it would make her feel better and researched on the Internet ways to obtain codeine exctracting it from the A-ferin® (codeine phosphate 10 mg, paracetamol 300 mg, chlorpheniramine maleate 2 mg) capsule. She extracted codeine from ∼ 80–120 capsules, obtaining it by the CWE method. To get the “high” effect she used intravenous and subcoutane administration. Her reported effects included initial light sedation, followed by a feeling of contentment, euphoria, and muscular relaxation; a general sense of well-being; and potent waves of warmth all over the body. Physical examination revealed a normally built girl with body weight and height at the 50th to the 75th percentile. Body mass index was 22 kg per m² (50th to 75th percentile), and her blood pressure was 118/80 mm Hg.

Her birth and development had been normal (no maternal alcohol/cigarette or illicit drug use). Buprenorphine 2 mg per day was given to the patient following sudden opiate withdrawal symptoms such as runny nose, lacrimation, and severe stomach pain. Early in detoxification, she had a lower migraine-like headache in the frontotemporal region. On day 7, she reported a throbbing and persistent frontal headache that was accompanied by photosensitivity, nausea, and vomiting. Her neurological examation was unremarkable. Ophthalmological examination showed bilateral papilledema but no retinal hemorrhages. A lumbar puncture showed a cerebrospinal fluid (CSF) opening pressure of 310 mm of water (normal <250) with normal biochemical and cytologic findings. MRI of the brain was normal. MR venography of the dural sinuses showed no evidence of thrombosis. CSF gram stain was negative for organisms, and culture remained without growth at 72 hours. CSF indices were as follows: Microprotein 27 mg/dL, glucose 63 mg/dL, Na 146 mEq/L, Cl 124 mEq/L, and normal immunoglobulin G (IgG) index (IgG index=0.51). The patient was evaluated by echocardiography and infective endocarditis was not considered. There was no thrombus. All routine biochemical tests were within the normal limits. Her thyroid hormone profile was normal. Serological tests were negative for hepatitis A-C viruses, Epstein-Barr virus, cytomegalovirus, Toxoplasma gondii, rubella virus, Mycoplasma pneumoniae, and Chlamydia pneumoniae. Vitamin A level (689 μg/L) and vitamin B12 level (209 pg/mL) were normal. The patient's visual acuity was 0,9 (−3) in the right eye and 1,0 (−2) in the left eye.

Acetazolamide, initiated at 750 mg per day, was slowly tapered. The observation was that the headache had been reversed by the renewed intake of suboxone and acetazolamide. After 1 week, the headache, vomiting, and visual blurring were improved. After 2 months, the patient was asymptomatic, with complete resolution of papiledema.

Discussion

In recent years, most codeine-containing cold preparations have been reported to lead to the serious social problem of pharmaceutical opioid abuse (Fischer et al. 2006; Hall and Mattick 2007), especially in adolescents. Misuse according to Dobbin and Tobin (2008) appears related to the increasing dose of codeine, which increases abuse potential and likelihood of adverse effects, even when combined with safer analgesics such as paracetamol. However, chronic abuse of this medicine can induce physical and psychological dependence.

Withdrawals in cases of physical dependency on codeine include classic opiate dependence symptomatologies such as certain idiopathic headaches. Opiate withdrawal can be associated with a frontotemporal, pulsating, long-lasting migraine- like headache (De Marinis et al. 1991). However, there is no literature associated with PC and opiate withdrawal. Although PC can be occur with multiple drugs' (such as coticosteroids) long-term use and sudden interruption, the pathophysiology of idiopathic intracranial hypertension is still not fully understood. Theoretically, PC is associated with “parenchymal oedema, Increased cerebral blood volume, excessive CSF production, compromised CSF resorption, venous outflow obstruction” (Skau et al. 2006). Clinical studies have found that long-term opioid use can affect cerebral blood flow patterns (Rose et al. 1996; Gerra et al. 1998). In our case, we did not find any association with previously reported relevant factors. Therefore, PC is thought to be associated with long-term use of codeine and withdrawal. We believe that awareness should be raised about the damage caused by medications containing codeine, because of the belief among young people that it is safe compared with other substances. Users who share their personal experiences on Internet forums pose a risk to adolescents in search of innovation. In light of this information, education of patients and parents about the dangers of these seemingly harmless OTC medications must be a top priority. Parents need to be aware of potential warning signs of abuse, such as frequent prescription refills, changes in behavior, and falling school performance. Healthcare professionals with deeper knowledge who are searching for the use of other illegal substances should be aware of the misuse and abuse potential of various codeine-containing medications.