BDNF is a regulator of drug addiction and psychological dependence. Indirect costs due to alcohol dependence are significant. Heroin also produces profound degrees of tolerance and physical dependence. This provides some protection against excessive alcohol consumption and alcohol dependence (alcoholism). Nicotine dependence involves tolerance, sensitization, physical dependence, and psychological dependence. Some symptoms associated with psychological dependence may also occur during withdrawal. These processes are thought to play a role in drug dependence and addiction. Buprenorphine treatment carries the risk of causing psychological or physical dependence. Not all withdrawal effects are evidence of true dependence or withdrawal. It is approved for treatment of moderate to severe pain as well as opioid dependence. Physical dependence and psychological dependence may also occur. More complex interaction laws introduce a weak temperature dependence. Long-term use of high doses of tramadol causes physical dependence and withdrawal syndrome. This was due in part to his increasing dependence on drugs. Long-term use can lead to alcohol abuse, cancer, physical dependence, and alcoholism.