Drug Tolerance/Dependence/Addiction/Withdrawal

This section has two purposes: First, to provide a series of scientific papers on the various aspects of toxicity exhibited by many drugs used in the therapy of CRPS/RSD/chronic pain. Second, to clarify the ever-present confusion about these terms and how they apply to certain drug situations, especially involving medications used for CRPS.


Addiction - Used interchangeably with dependence, addiction is defined as "when an individual persists in use of alcohol or other drugs, or engaging in certain behaviors, despite problems related to use of the substance, substance dependence may be diagnosed." Compulsive and repetitive use may result in tolerance to the effect of the drug and withdrawal symptoms when use is reduced or stopped. This, along with Substance Abuse are considered Substance Use Disorders." Addiction is a primary illness, which follows a predictable course and responds to treatment similarly across many patient populations.

It should be stressed that the non-substance addictions and compulsions are just as serious as substance-based addictions, and can be just as fatal. These include gambling, sex, eating, codependency, and many more. The best definition of addiction I've heard is this: "Addiction is the condition of compulsively repeating any behavior that causes us shame."

Dependence - see Addiction.

Tolerance - A physiological adaptation to the use of certain drugs over an extended period of time, resulting in a need for markedly increased amounts of the substance to achieve intoxication or desired effect, and/or a markedly diminished effect with continued use of the same amount of the substance. Unrelated to dependence or addiction.

Withdrawal - the group of symptoms that occur upon the abrupt discontinuation or decrease in intake of medications or recreational drugs for which tolerance has set in. It is thus a physiological phenomenon, and will thus be experienced by most long-term users of any drug that produces tolerance. Thus, like tolerance, it is unrelated to addiction.

The severity, perception of severity, and duration of withdrawal symptoms depend heavily on the specific drug(s), time span of drug use prior to discontinuation, dose at discontinuation, the personality of the user, whether addiction has set in, and other factors.

In this compilation of papers, I decided to forgo my usual practice of commenting, essentially describing what the article is all about. These titles are so uncharacteristically clear that I decided to leave out the comments. If you have an opinion as to whether you prefer the comments be included in any case, please let me know.

Scientific Articles
Title (& link)
Journal Citation
Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data
Addiction 2003, 98, 1371
Abuse liability, behavioral pharmacology, and physical-dependence potential of opioids in humans and laboratory animals: Lessons from tramadol
Biol. Psych. 2006, 73, 90
Antiepileptic Drug Withdrawal: Literature Review
Mayo Clin. Proc. 2002, 77, 1378
Craving of Prescription Opioids in Patients With Chronic Pain: A Longitudinal Outcomes Trial
J. Pain 2012,13,146
Dependence potential of antidepressants compared to benzodiazepines
Prog. Neuropsychopharm.
Biol. Psych. 2002, 26, 939
Does Report of Craving Opioid Medication Predict Aberrant Drug Behavior Among Chronic Pain Patients?
Clin. J. Pain 2009, 25, 193
Focal nonconvulsive seizures during detoxification for benzodiazepine abuse
Epilepsy & Behavior 2012, 23, 168
Is There a Recreational Misuse Potential for Pregabalin? Analysis of Anecdotal Online Reports in Comparison with Related Gabapentin and Clonazepam Data
Psychother. Psychosom. 2011, 80, 118
Long-term outcome after discontinuation of benzodiazepines for insomnia: a survival analysis of relapse
Behav. Res. Ther. 2005, 43, 1
Medication-overuse headache and opioid-induced hyperalgesia: A review of mechanisms, a neuroimmune hypothesis and a novel approach to treatment
Cephalalgia 2012, 33, 52
Pain and Opioid Addiction: What is the Connection? Curr. Pain Headache Rep. 2010, 14, 17
Pregabalin for the discontinuation of long-term benzodiazepines use: An assessment of its effectiveness in daily clinical practice Europ. Psych. 2012, 27, 301
Pain 2010, 150, 390
Venlafaxine dependence in a patient with a history of alcohol and amineptine misuse Addiction 2008, 103, 1572

The Special Case of Benzodiazepine Addiction

Everyone knows that benzodiazepines ("benzos") can be addictive (they're C-IV), but little hard data are available to the benzo-taking public, and the entire world consumes benzos at a rate that's just incredible. As with so many other drugs, the pharmas that develop and market the drugs want to accentuate their positive aspects and play down, if not ignore completely, their drawbacks.

What moved me to include this section* is that benzo withdrawal can be more than feeling just horrible for days; there are at least two benzos, withdrawal from which has resulted in fatalities, which is NOT common for drug withdrawals. Xanax is the worst of these and, ironically, is the most prescribed benzo on the market. And lots and lots of CRPS patients take Xanax in large quantities.

2011 rank
2009 rank
2005 rank
#US Scripts
% Change from 2009
alprazolam (Xanax®)
+ 9%
lorazepam (Ativan®)
+ 4%
diazepam (Valium®)
+ 6%
buspirone (Buspar®)*
+ 15%
* Buspirone is not a benzodiazepine, in either structure or mode of action. However, its efficacy in controlling long-term anxiety causes it often to be compared with actual benzos. It is not addictive.

* These data were acquired from an article from the very good psychcentral.com site; the specific article can be accessed here. It covers many other psychoactive drugs other than the benzos highlighted here.

There is a single BZ antagonist approved by the FDA, called flumazenil, but it has not found use yet in BZ detoxification or addiction treatment.

Medicalnewstoday.com maintains a list of useful links for those wishing further information, or those who feel like they may need help in this potentially very dangerous area.