The effectiveness of a given dose of an opioid drug declines with its repeated administration in the presence of intense pain. This loss in effectiveness is called tolerance . Evidence suggests that tolerance is not due to alterations in the brain’s responses to drugs. Animals exhibiting tolerance to morphine after repeated injections in a familiar environment show little or no tolerance when given the same doses and tested for pain sensitivity in new environments . Thus, there is almost certainly a learned aspect of tolerance. The cellular and molecular mechanisms underlying this loss of responsiveness are not clear. Physical dependence and addiction in a person using intravenous administration closely follow the dynamics of drug tolerance; increasing doses are required to produce the psychological effects, while tolerance protects the brain against the respiratory depressant actions of the drug. In the tolerant individual, intense adverse reactions can be precipitated by administration of an opioid antagonist, thus revealing the dynamic internal equilibrium that previously appeared to neutralize the response of the brain to the opioids. The signs of the withdrawal response (., anxiety , tremors, elevation of blood pressure , abdominal cramps, and hyperthemia) can be viewed as signs of an activated sympathetic nervous system and to some extent an extreme, but nonspecific, arousal response.
In the 1990s, researchers discovered that two different COX enzymes exist: COX-1 and COX-2. COX-1 is present in most tissues, including the stomach lining. It’s also involved in kidney function. COX-2 is the enzyme primarily present at sites of inflammation . Both COX-1 and COX-2 convert arachidonic acid to prostaglandin, resulting in pain and inflammation. The anti-inflammatory action of NSAIDs is mainly due to inhibition of COX-2, and their unwanted side effects (like bleeding ulcers) are largely due to inhibition of COX-1. ( 12 )