Intrathecal (IT) drug therapy has been established as an effective treatment option for patients with chronic pain of malignant or non-malignant origin, with an established safety profile and fewer adverse effects compared to oral or parenteral pain medications. Morphine (a μ-opioid receptor agonist) and ziconotide (a non-opioid calcium channel antagonist) are the only IT agents approved by the US Food and Drug Administration for the treatment of chronic pain. Although both are considered first-line IT therapies, each drug has unique properties and considerations. Areas Covered: This review will evaluate the pivotal trials that established the use of morphine and ziconotide as first-line IT therapy for patients with chronic pain, as well as safety and efficacy data generated from various retrospective and prospective studies. Expert Opinion: Morphine and ziconotide are effective IT therapies for patients with chronic malignant or non-malignant pain that is refractory to other interventions. IT ziconotide is recommended as first-line therapy due to its efficacy and avoidance of many adverse effects commonly associated with opioids. The use of IT morphine is also considered first-line; however, the risks of respiratory depression, withdrawal with drug discontinuation or pump malfunction, and the development of tolerance require careful patient selection and management.