Objectives The aim of this research is to systematically define non-parenteral routes of administration of opioid analgesics and their effect on the pharmacokinetic properties and therapeutic indications and to define the principles of development of delivery systems for non-parenteral usage of opioid analgesics for improved treatment of severe acute and chronic pain. Hypothesis: Developement of appropriate drug delivery system enables the optimization of the pharmacokinetic profile and the treatment outcome. New non-parenteral drug delivery systems of opioid analgesics allow better control of analgesia, reduction of side effects, improved adherence, improved safety profile and new indications of existing active pharamaceutical ingredients. Material and Methods Targeted literature search was done on MEDLINE / PubMed, ScienceDirect, Google Scholar, the database of the National and University Library (database with a national license and the license of the University of Zagreb), databases of regulatory agencies (EMA, FDA, HALMED). Targeted literature search was also done on guidelines for the treatment of pain of European Collaboration for Research Palliative Care (EPCRC) and the European Association for Palliative care (EAPC). Searching the database of clinical trials from the National Institutes of Health USA (NIH), PubMed database and EU clinical trials database provided an overview of the clinical trials of opioid analgesics. In targeted literature search, key words were used independently or connected with logic operator AND to yield data on the route of administration, development, clinical trials and registered non-parenteral formulations of opioid analgesics. In addition to electronic databases, the available scientific and professional literature was used for research on specific issues of particular routes of administration of opioid analgesics. This thesis presents and analyzes the fundamental physiology of pain and the effects of opioid analgesics on a cellular level, the regulatory requirements for the development of new developing non-parenteral forms of opioid analgesics, guidelines on the treatment of pain, history and current development (R&D) of non-parenteral use of opioid analgesics (related to the physiological, anatomical and histological properties of each route of administration) and registered products of opioid analgesics. Results Development of innovative drug formulations and medicinal devices enabled non-parenteral administration of opioid analgesics. Non-parenteral routes of administration include transdermal, intranasal, and oral transmucosal delivery of the opioid analgesic. Pulmonary administration of opioid analgesics exists only as a research concept, and there is no approved medicinal products for pulmonary route of administration. Transdemal delivery of opioid analgesics is suitable for long-term analgesia of baseline severe pain, and replaces the infusion as the main route of administration of analgesics. Transdermal delivery is suitable for use outside the clinic. Pharmacokinetic properties of intranasal and oral transmucosal administration (sublingual and buccal) enable treatment of severe breakthrough pain, usually malignant pain. Anatomical, morphological and histological characteristics of each route of administration and drug formulation define pharmacokinetic properties and thus determine the indications for clinical use. Conclusion The route of administration and the pharmaceutical formulation affect the pharmacokinetic profile of the used opioid analgesic. Innovative non-parenteral formulations of opioids and medical devices for opioid analgesic administration provide better control of analgesia, reduce side effects, enable better adherence, are safer to use and provide new clinical indications of existing active pharmaceutical substances. It is very important to recognise the critical properties of innovative drug delivery systems. The outcome of pain management and the individualization of pain management depend on the ability of improvement of critical properties of innovative drug delivery systems.