Opioids are broad spectrum analgesics that may be beneficial to alleviate the intense perception of algesia in patients suffering with pain. They have been one of the most controversial analgesics, in part because of their potential for addiction. Opioids or any currently available analgesic will not provide effective analgesia for every patient with chronic neuropathic pain (NP), but overall opioids are considered to be a second or third line class of analgesics that may provide reasonable analgesia to some patients with chronic NP. Although opioids may alleviate chronic NP, overall, NP tends to be less opioid responsive than nociceptive pain. The mechanisms that may contribute to neuropathic pain may simultaneously also contribute to diminishing the antinociceptive properties of opioids for neuropathic pain. Some of these mechanisms may also contribute to analgesic tolerance and/or opioid-induced hyperalgesia. Hyperalgesia consequently to nerve insult and opioid-induced analgesic tolerance, may both involve the N-methyl-D-aspartate (NMDA) receptor and share part of intracellular events producing a state of neural hyperexcitation. Conversely, opioid therapy may contribute to nociceptive processes that may be involved in neuropathic pain such as opioid-induced cholecystokinin release. Furthermore, within NP, peripheral NP appears to be the most opioid responsive, followed by spinal NP while supraspinal NP tends to be the least responsive to opioids. Although, there is no robust evidence that any specific opioid agent is better than any other opioid at effectively treating NP, it is conceivable that some opioids/opioid-like analgesic agents may be particularly well suited to alleviate NP in certain patients suffering from neuropathic pain.