Since the late 1990s, the prescription of opioid medications has increased as a consequence of extensive misuse of opioids; however, the highly addictive nature of opioids has been overlooked. In 2017, the United States Department of Health and Human Services declared the opioid crisis an emerging public health challenge. It's crucial to note that opium serves as the primary constituent of opioids. Moving beyond the immediate risks associated with opium misuse, which include withdrawal syndrome and acute side effects, recent long-term health studies have uncovered a potential link between opium use, the fundamental ingredient of opioids, and an elevated cancer risk (Kamangar et al., 2014, Sheikh et al., 2020, Sheikh et al., 2020). The International Agency for Research on Cancer (IARC) affirmed that opium is carcinogenic to humans (Group 1) for urinary bladder, laryngeal, and lung cancers (Warnakulasuriya et al., 2020). limited available data for other subsites of head and neck cancer (HNC), including the lip, oral cavity, and pharynx, poses a challenge for researchers to establish a consensus on the association between opium use and HNC subsites (Alizadeh et al., 2020, Bakhshaee et al., 2017, Nalliah et al., 2018, Razmpa et al., 2014, Saedi et al., 2012, Sheikh et al., 2020).

Opium is extracted and dried from the opium poppy (Papaver somniferum) plant, comes in various forms, with raw opium being the most common. However, refined opium and dross are also utilized. The most common opioid drug that is intravenously abused is heroin. Other known abused opioid substances include opium, methadone, and prescription opioids. A load of alkaloids determines the carcinogenicity of opium use (Mohebbi et al., 2019); additionally, the incomplete combustion of coal used in opium evaporation exposes users to polycyclic aromatic hydrocarbons (PAHs). PAH's metabolites can produce DNA adducts, leading to DNA mutations, alteration of gene expression profiles, and tumorigenesis (Etemadi et al., 2020).

A possible association between opioid use and specific malignancies was previously suggested by sparse reports (Grinshpoon et al., 2011, Khoo, 1981, Mohebbi et al., 2021, Mousavi et al., 2003, Shoffel‐Havakuk et al., 2018). Recognizing the association between opium and specific malignancies is important. It can help identify high-risk populations and may also have an important role in the management of these oncologic patients since current pain control in oncologic patients often includes opioid agents (Cata et al., 2014, Cata et al., 2015).

Based on the limitations of previous studies, a comprehensive search strategy through main academic databases and gray literature was designed to gather evidence with head and neck cancer subsites (M. Filho et al., 2023, Singh et al., 2021). With consideration of the literature gaps mentioned above, the current systematic review aimed to estimate HNC among opium users with subgroup analysis considering characteristics including subsites of HNC, and opium definition.