Hydrocodone is by far the most prescribed drug in the USA. A review of laboratory issues related to pain management is provided. The article reports that hydrocodone is by far the most prescribed drug in the USA, and has been for several years. Even as the use of oxycodone and methadone for pain management has increased, screening assays have not been available until recently. Moreover, screening assays are still not available for tramadol, fentanyl, and newer benzodiazepines. Problems such as cross reactivity and false negatives with screening assays have failed the clinicians trying to management pain patients. One solution has been to employ newer LC-MS/MS technology. Expensive and requiring significant technical expertise to operate, this technology is still all too rare. Laboratories and industry still have improvements to make.