Neuroadaptation interferes with the ability of opioids to provide long-term analgesia, especially when given continuously, and may actually produce opposite effects such as increasing existent pain or facilitating the development of chronic pain by activating endogenous counter-regulatory systems. Opioids are natural or synthetic substances that bind to opiate receptors. An opiate is a drug derived from opium—from the poppy plant Papaver somniferum. Morphine, codeine, thebaine, and papaverine are examples of opiates. Worsening pain routinely occurs during the treatment of chronic pain states with opioid analgesics. Tolerance describes a pharmacologic experience where the same dose of medication results in a diminished physiologic response—this can be in regard to analgesia or in the experience of side effects. The non-opioid orexin pathway also plays a role in the development of opioid tolerance. Blocking orexin pathways prior to initiating opioid exposure can prolong the onset of opioid tolerance.