Medication overuse and drug addiction: a narrative review from addiction perspective

DOI: https://doi.org/10.1186/s10194- 021- 01224- 8

Abstract-Summary Chronic headache is particularly prevalent in migraineurs and it can progress to a condition known as medication overuse headache (MOH).

MOH is a secondary headache caused by overuse of analgesics or other medica-

tions such as triptans to abort acute migraine attacks.

The worsening of headache symptoms associated with medication overuse (MO) generally ameliorates following interruption of regular medication use, although the primary headache symptoms remain unaffected.

We aimed to identify features in MO and drug addiction that may correlate. We initiate the review by introducing the classes of analgesics and medications

that can cause MOH and those with high risk to produce MO.

Background Most sufferers are individuals at their most productive ages [474] and thus, prevent- ing the development of secondary disorders as well as finding novel treatments especially for those suffering with chronic headache are important to maintain workforce productivity and quality of life.

The ICHD-3 defines medication overuse headache (MOH) as a secondary head- ache that develops from the use of (I) triptans, ergotamine, opioids, or combination- analgesics of two or more classes for at least 10 days a month for > 3 months, or (II) non-steroidal anti-inflammatory drugs (NSAIDs) or paracetamol for at least 15 days a month for > 3 months [16].

MOH is often the result of the progression of long-standing chronic headache

disorders, and mostly CM [475].

Whether MOH is a secondary headache originated by the condition of medica- tion overuse (MO) or MO is a consequence of chronic headache disorders remains a matter of debate [476].

In the present review, we will focus on the condition of medication overuse (MO)

irrespective of the underlying headache.

Medications to Abort Headache Attacks Specific medications include triptans and ergotamine, which are usually prescribed for migraine and cluster headaches.

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Non-specific medications comprise of various active compounds with different

mechanism of actions.

At the cellular level, opioids reduce the overall synaptic transmission as well as inhibit the GABAergic signaling in the brain stem, which results in the inhibition of the pain circuit signaling [477].

Specific and non-specific medications can both cause MO. Patients treated with triptans or opioids are more frequently reported with MO at a shorter time than those undertaking treatments with other medications [478, 479]. Triptans produce MO in approximately 1.7 years and opioids, in approximately

4.8 years [480].

NSAIDs and paracetamol exhibit the lowest risk for MO as it is less frequently

reported [478, 481, 482].

Europe has also seen an increase in opioid prescriptions in recent years [483] and

that brings along fears for an imminent opioid misuse in Europe.

MO and Drug Addiction: The Overlapping Features MO and drug addiction initiate from different contexts and reasons.

The development of drug addiction in individuals is associated with risk factors

and some risks factors for MO and addiction may overlap.

Based on the ability of DA in changing the perception of pain in chronic pain patients as well as in altering the motivation for reinforcing activities, it is very likely that the psychological attachment to the drug by MO patients is contributed or governed by DA.

For MO, the type of primary headache and the class of the drug overused by the patient, i.e. opioids and barbiturates [484], the baseline headache frequency [485], and the number of previous preventive treatments [486] have all being associated as predictors to relapse.

MO patients show behaviors such as typical fear of headache attacks - cephalal- giaphobia -, anticipatory anxiety, obsessional or ritualized drug-taking behaviors, psychological drug attachment, and abstinence symptoms after drug discontinua- tion [487].

Common Systems in MO and Drug Addiction Evidence from both animal and human studies suggests that MO patients have higher excitability of the nociceptive pathways during and between migraine attacks, leading to cutaneous allodynia [479].

These studies suggest that, while the analgesic efficacy is correlated with an increase in platelet 5-HT levels, the normalization of platelet 5-HT levels as well as the changes in the 5-HT density after prolonged analgesic administration may be associated with increased headache frequency.

DaSilva and others (2017) demonstrated imbalance of DA D2/D3 receptors dur- ing migraine attacks and neuroimaging studies have revealed dysfunctions in the mesocorticolimbic dopamine circuit in MO patients [488].

The available fMRI studies show that patients with MO, compared with episodic migraine, have altered connectivity in regions of the pain reward system, including the nucleus accumbens, putamen, caudate, hippocampus, periaqueductal gray,

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precuneus, and the insula, suggesting that MO might involve the same brain areas as drug addiction [489].

Treatments of MO While recently the combination of withdrawal and preventive medication was rec- ommended as the most successful treatment of MOH [490], multiple studies have suggested withdrawal as the primary treatment of choice for MO [491–493].

Inpatient treatment should be offered to complex cases such as patients overus- ing opioids or barbiturates, those who show psychological problems, severe medical comorbidities, failures from previous withdrawal treatments and/or those with severe withdrawal symptoms [481, 491].

Abrupt withdrawal without tapering is advisable for patients overusing simple analgesics, ergotamine, and triptans, while tapering is recommended for those under opioids or barbiturate treatments [207, 481].

Patient’s engagement and behavioral interventions are both necessary for suc-

cessful treatment.

If a MO patient shows any signs of addictive behaviors a psychiatrist specialized

in addiction should be engaged to initiate other relevant treatments [494].

Opioids are among the most difficult drugs to withdraw [491, 494] and, there- fore, psychiatrists could provide additional assistance and support to increase the success rate and prevent relapses.

Conclusions Several studies support that MO shares certain behavioral, genetic, and neuronal pathways with drug addiction.

DA could either lead to an increase in the risk for MO or to the manifesta-

tion of MO.

Chronic headache patients holding similar risks to addiction should be followed up with more discretion to prevent the development of MO and addictive behaviors. Combined psychological and pharmacological interventions can also increase

the success rate for MO patients in remission.

Further studies are still warranted to clarify the role of DA in MO, as well as to understand the molecular mechanisms of chronic use of medications in the develop- ment of the secondary headache disorder such as MO.

Acknowledgement A machine generated summary based on the work of Takahashi, Tatiane Teru; Ornello, Raffaele; Quatrosi, Giuseppe; Torrente, Angelo; Albanese, Maria; Vigneri, Simone; Guglielmetti, Martina; Maria De Marco, Cristiano; Dutordoir, Camille; Colangeli, Enrico; Fuccaro, Matteo; Di Lenola, Davide; Spuntarelli, Valerio; Pilati, Laura; Di Marco, Salvatore; Van Dycke, Annelies; Abdullahi, Ramla Abuukar; Maassen van den Brink, Antoinette; Martelletti, Paolo; 2021  in The Journal of Headache and Pain.

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Factors associated with acute medication overuse in people with migraine: results from the 2017 migraine in America symptoms and treatment (MAST) study