Opioid Tolerance
Ketamine for acute and subacute pain in opioid-tolerant patients.
J Opioid Manag. 2008 May-Jun;4(3):173-80 
Chazan S, Ekstein MP, Marouani N, Weinbroum AA.

Acute Pain Service, Tel Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Prolonged acute pain, especially that of oncologic neurological origin, is at times difficult to control; it is seldom entirely alleviated by opioids. We report eight patients with severe pain, three of whom suffered from new onset oncologic metastatic bone pain, others had previous pain syndromes and presented with exacerbation of pain. Pain was associated with hyperalgesia and allodynia phenomena in two patients and with phantom pain in a third one. Tolerance to opioids had developed, and high IV doses of morphine, meperidine or fentanyl, and patient-controlled intravenous and epidural analgesia were insufficient. Several patients became dependent on opioids and could not be weaned from assisted ventilation. Pain was controlled with decreasing adjunct doses of ketamine. Within 5-10 days of ketamine and opioid protocols, pain was controlled and after an additional 5-7 days, ketamine could be stopped and pain controlled on oral regimens compatible with outpatient care. Ketamine is an efficient adjuvant analgesic for intractable severe pain, caused by metastasis, trauma, chronic ischemia, or central neuropathic pain. It is effective even when mega doses of IV, epidural, or oral opioids prove ineffective and when signs of tolerance have developed.

PMID: 18717513 [PubMed - in process] 

Effective treatment of severe cancer pain of the head using low-dose ketamine in an opioid-tolerant patient.
J Pain Symptom Manage. 1995 May;10(4):310-4.
Clark JL, Kalan GE.

Department of Anesthesiology, Greenwich Hospital, Connecticut, USA.

We report the case of a 39-year-old man with severe pain due to unresectable squamous-cell carcinoma of the maxillary sinus that had invaded cranial bone and had metastasized to the cervical spine. Tolerance to opioids had developed, and high doses of transdermal, continuous intravenous, and epidural opioids did not control his pain. An acute episode of extremely severe head pain was immediately controlled with a subanesthetic dose of ketamine after failure of a stress dose of corticosteroid and intravenous lidocaine. Because the patient was terminally ill and invasive procedures were not options, we controlled his pain using a low-dose ketamine infusion until his death 13 days later. Ketamine may be a good co-analgesic for breakthrough pain and for severe pain caused by terminal cancer when invasive techniques are inappropriate. Its mechanism of action may include reversal of opioid tolerance in addition to an inherent analgesic effect.

PMID: 7541437 [PubMed - indexed for MEDLINE] 

Ketamine as an adjuvant for treatment of cancer pain in children and adolescents.
J Pain. 2007 Jun;8(6):515-21. Epub 2007 Apr 16.
Finkel JC, Pestieau SR, Quezado ZM.

Division of Anesthesiology and Pain Medicine, Children's National Medical Center, George Washington University School of Medicine, Washington, DC 20010, USA. jfinkel@cnmc.org

In children with advanced stages of cancer, pain control remains inadequate in many patients and a solution to this problem is sorely lacking. Factors related to progression of the primary disease and side-effects of high doses of opioids, the mainstay of pain therapy, contribute to the inadequacy of pain control. In addition, few studies suggest that opioids, by inducing tolerance, having pronociceptive effects and producing hyperalgesia in some patients, can also contribute to inadequacy of pain control. Researchers have shown that N-methyl-D-aspartate (NMDA) receptor antagonists may have a role in mitigating opioid-induced tolerance and hyperalgesia in adults. However, literature on NMDA antagonists to treat cancer pain in children and adolescents is scarce. We used subanesthetic doses of ketamine to treat 11 children and adolescents who were on high doses of opioids and yet had uncontrolled cancer pain. A low-dose ketamine infusion was administered to all patients to modulate the need for rapidly escalating opioid therapy. We found that in 8 of 11 patients, ketamine infusions used as an adjuvant to opioid analgesia was associated with opioid-sparing effects and apparent improvement in pain control and in the children's ability to interact with their family. This study suggests that infusions of ketamine may offer a promising therapeutic option in the treatment of appropriately selected children and adolescents with intractable cancer pain. PERSPECTIVE: In many children with advanced stages of cancer, pain control remains inadequate. We used subanesthetic doses of ketamine to treat 11 children and adolescents who were on high doses of opioids and had uncontrolled cancer pain. In the majority of patients, ketamine appeared to improve pain control and to have an opioid-sparing effect.

PMID: 17434801 [PubMed - indexed for MEDLINE 

Successful use of ketamine for intractable cancer pain.
Support Care Cancer. 2005 Mar;13(3):188-93. Epub 2004 Oct 6.
Lossignol DA, Obiols-Portis M, Body JJ.

Institute Jules Bordet, Clinique des Soins Supportifs et des Soins Palliatifs, Service de médecine interne, Université Libre de Bruxelles, 1 Rue Héger Bordet, 1000, Brussels, Belgium. dominique.lossignol@bordet.be

GOALS AND WORK: Despite medical awareness, intractable pain is a serious problem in cancer and occurs in up to 2% of advanced cancer patients. However, few data are available concerning the optimal treatment of such patients. The emergence of intractable pain may notably be due to the activation of N-methyl-D-aspartate (NMDA) receptors located in the central nervous system. NMDA antagonists might thus be an interesting approach in such pain syndromes. PATIENTS AND METHODS: Twelve patients with intractable cancer pain received a test dose of 5-10 mg of ketamine, a strong NMDA antagonist, in order to determine their response and tolerance to the drug. Continuous intravenous infusions of ketamine associated with morphine were then administered. MAIN RESULTS: The acute test dose was successful in all cases (VAS <3/10 after 5 min). The prolonged use of ketamine allowed us to reduce the total daily dose of morphine required (range: 200-1,200 mg) by 50% and allowed eight patients to go home with a portable pump with morphine and ketamine during a relatively long period of time (range: 7-350 days, median: 58 days). Side effects were moderate (dizziness) and they were limited to the test phase. CONCLUSION: Our data suggest the importance of NMDA receptors in the genesis of chronic cancer pain and indicate that NMDA antagonists should be further studied for the management of cancer pain and, in particular, intractable pain.

PMID: 15480820 [PubMed - indexed for MEDLINE

Opioid-induced hyperalgesia: pathophysiology and clinical implications.
J Opioid Manag. 2008 May-Jun;4(3):123-30.
Mitra S.

Department of Anaesthesia & Intensive Care, Government Medical College & Hospital, Chandigarh, India. drsmitra12@yahoo.com

BACKGROUND: Opioid-induced hyperalgesia (OIH) refers to a phenomenon whereby opioid administration results in a lowering of pain threshold, clinically manifest as apparent opioid tolerance, worsening pain despite accelerating opioid doses, and abnormal pain symptoms such as allodynia. AIM: The current review, while providing a clinically oriented updated overview on the pathophysiology of OIH, focuses predominantly on evidence-based clinical and management aspects of this important and often baffling phenomenon. METHOD: Online and manual search using key words such as opioid-induced hyperalgesia, opioid-induced abnormal pain sensitivity, opioid hyperalgesia, opioid-induced paradoxical pain, or opioid-induced abnormal pain, followed by full-text access and further crossreferencing. RESULTS: The underlying pathophysiology of this phenomenon, although still unclear, appears to be related to an opioid-induced imbalance between the internal antinociceptive and pronociceptive systems. Clinical differentiation of an apparent opioid tolerance state includes OIH. Once diagnosed or provisionally considered, treatment strategies could include opioid dose reduction, opioid rotation, use of agents with NMDA receptor antagonism, and a properly timed coxib. CONCLUSION: Despite initial skepticism and reservations, the phenomenon of OIH in humans is now accepted a clinical reality and a challenge faced by anesthesiologists, intensivists, pain specialists, and other workers in a diverse range of settings from perioperative care to palliative care medicine.

PMID: 18717507 [PubMed - in process] 

Opioid-induced hyperalgesia in humans: molecular mechanisms and clinical considerations.
Clin J Pain. 2008 Jul-Aug;24(6):479-96.
Chu LF, Angst MS, Clark D

Department of Anesthesia, Stanford University School of Medicine, Stanford, CA 94305-5640, USA.

Opioid-induced hyperalgesia (OIH) is most broadly defined as a state of nociceptive sensitization caused by exposure to opioids. The state is characterized by a paradoxical response whereby a patient receiving opioids for the treatment of pain may actually become more sensitive to certain painful stimuli. The type of pain experienced may or may not be different from the original underlying painful condition. Although the precise molecular mechanism is not yet understood, it is generally thought to result from neuroplastic changes in the peripheral and central nervous systems that lead to sensitization of pronociceptive pathways. OIH seems to be a distinct, definable, and characteristic phenomenon that may explain loss of opioid efficacy in some cases. Clinicians should suspect expression of OIH when opioid treatment effect seems to wane in the absence of disease progression, particularly if found in the context of unexplained pain reports or diffuse allodynia unassociated with the pain as previously observed. This review highlights the important mechanistic underpinnings and clinical ramifications of OIH and discusses future research directions and the latest clinical evidence for modulation of this potentially troublesome clinical phenomenon.

PMID: 18574358 [PubMed - indexed for MEDLINE 

Formulation and evaluation of dextromethorphan hydrobromide sustained release tablets.
Drug Deliv. 2008 Sep;15(7):429-35.
Meyyanathan SN, Rajan S, Muralidaharan S, Siddaiah MK, Krishnaraj K, Suresh B.

Department of Pharmaceutical Analysis, JSS College of Pharmacy, Rocklands, Ootacamund-643 001, India.

Sustained release (SR) matrix tablets of dextromethorphan hydrobromide were prepared by wet granulation using hydroxypropyl methyl cellulose (HPMC-K-100 CR) as the hydrophilic rate controlling polymer. The effect of the concentration of the polymer and different fillers on the in vitro drug release rate was studied. The studies indicated that the drug release can be modulated by varying the concentration of the polymer and the fillers. A complete cross-over bioavailability study of the optimized formulation of the developed sustained tablets and marketed immediate release tablets was performed on six healthy male volunteers. The extent of absorption of drug from the SR tablets was significantly higher than that for the marketed dextromethorphan hydrobromide tablet because of lower elimination rate and longer half-life.

PMID: 18712620 [PubMed - in process

Dextromethorphan: a review of N-methyl-d-aspartate receptor antagonist in the management of pain.
CNS Drug Rev. 2007 Spring;13(1):96-106.
Siu A, Drachtman R.

Department of Pharmacy Practice and Administration, The Ernest Mario School of Pharmacy, Rutgers the State University of New Jersey, Piscataway, New Jersey 08854, USA. anitasiu@rci.rutgers.edu

Dextromethorphan (DM) is a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, which is widely used as an antitussive agent. DM also prevents neuronal damage and modulates pain sensation via noncompetitive antagonism of excitatory amino acids (EAAs). DM has been found to be useful in the treatment of pain in cancer patients and in the treatment of methotrexate-induced neurotoxicity. Clinical studies with DM in cancer patients are reviewed in this article.

PMID: 17461892 [PubMed - indexed for MEDLINE]