Opioids, Pain, And Palliative Care [6.3.9]
Curator: Stephen J. Williams, Ph.D.
As written by Hrachya Nersesyan and Konstantin V Slavin in Current approach to cancer pain management: Availability and implications of different treatment options in Ther Clin Risk Manag. 2007 Jun; 3(3): 381–400
According to statistics published by the American Cancer Society in 2002, “50%–70% of people with cancer experience some degree of pain” (ACS 2002), which usually only intensifies as the disease progresses. Less than half get adequate relief of their pain, which negatively impacts their quality of life. The incidence of pain in advanced stages of invasive cancer approaches 80% and it is 90% in patients with metastases to osseous structures (Pharo and Zhou 2005).
Mediators of pain and inflammation are known to be secreted from tumor cells as well as infiltrating immune cells, activating and sensitizing primary afferent nociceptors (nociceptive pain) and damaging the nervous system (neuropathic pain). However, there has been difficulty in modeling cancer-induced pain in animals. This has hampered our understanding and therapeutic intervention of the clinical situation, especially concerning ovarian cancer patients. It has been shown that 85% of ovarian cancer patients in palliative care (during last two months of life) still report severe pain although 54% of these women were given high intensity pain medications such as morphine, still the mainstream pain medication for severe cancer-associated pain. Admittedly, more research into the ability of cancer to provoke pain and sensitize the central nervous system, is warranted, as well as development of new methods of analgesia for cancer-associated pain at end-of-life. Therefore, in collaboration with several colleagues, in vivo models of nociceptive and neuropathic pain will be integrated with my co-developed in vivo tumor models of ovarian cancer. This tumor model allows for noninvasive monitoring of tumor burden without the need for anesthesia, as necessitated by imaging strategies to quantitate tumor burden, such as bioluminescence and MRI.
Even in an era of promising new cancer therapies, cancer pain is one of the highest concerns for the patient, their clinician, and surrounding loved ones, especially impacting quality of life during palliative care. Over half of cancer patients have reported severe pain in the course of their disease (List MA J Clin Oncol 2000 18:877-84) and the statistics are worse for ovarian cancer patients, regardless whether during treatment or in palliative care (see below review).
Journal of Pain and Symptom Management Volume 33, Issue 1 , Pages 24-31, January 2007
Pain Management in the Last Six Months of Life Among Women Who Died of Ovarian Cancer
Sharon J. Rolnick, PhD, MPH, Jody Jackson, RN, BSN, Winnie W. Nelson, PharmD, MS, Amy Butani, BA, Lisa J. Herrinton, PhD, Mark Hornbrook, PhD, Christine Neslund-Dudas, MA, Don J. Bachman, MS, Steven S. Coughlin, PhD
HealthPartners Research Foundation (S.J.R., J.J., A.B.), Minneapolis, Minnesota; Applied Health Outcomes (W.W.N.), Palm Harbor, Florida; Division of Research (L.J.H., D.J.B.), Kaiser Permanente Northern California, Oakland, California; Kaiser Permanente Center for Health Research (M.H.), Portland, Oregon; Josephine Ford Cancer Center (C.N.-D.), Henry Ford Health System, Detroit, Michigan; and National Center for Chronic Disease Prevention and Health Promotion (S.S.C.), Centers for Disease Control and Prevention, Atlanta, Georgia, USA
Abstract Previous studies indicate that the symptoms of many dying cancer patients are undertreated and many suffer unnecessary pain. We obtained data retrospectively from three large health maintenance organizations, and examined the analgesic drug therapies received in the last six months of life by women who died of ovarian cancer between 1995 and 2000. Subjects were identified through cancer registries and administrative data. Outpatient medications used during the final six months of life were obtained from pharmacy databases. Pain information was obtained from medical charts. We categorized each medication based on the World Health Organization classification for pain management (mild, moderate, or intense). Of the 421 women, only 64 (15%) had no mention of pain in their charts. The use of medications typically prescribed for moderate to severe pain (“high intensity” drugs) increased as women approached death. At 5–6 months before death, 55% of women were either on no pain medication or medication generally used for mild pain; only 9% were using the highest intensity regimen. The percentage on the highest intensity regimen (drugs generally used for severe pain) increased to 22% at 3–4 months before death and 54% at 1–2 months. Older women (70 or older) were less likely to be prescribed the highest intensity medication than those under age 70 (44% vs. 70%, P<0.001). No differences were found in the use of the high intensity drugs by race, marital status, year of diagnosis, stage of disease, or comorbidity. Our finding that only 54% of women with pain were given high intensity medication near death indicates room for improvement in the care of ovarian cancer patients at the end of life.
Cancer pain is a complexity concerning not only the peripheral and central nervous systems but the cancer cell, the tumor microenvironment, and tumor infiltrating immune cells and inflammatory mediators. The goal of this article is to briefly introduce these factors governing pain in the cancer patient and a discussion of animal models of pain in relation to cancer.
Pain is considered as either termed nociceptive pain (activations and sensitization of primary afferent “nociceptor” neurons or neuropathic pain (damage to sensory nerves). Mediators of pain and inflammation are known to be secreted from tumor cells as well as infiltrating immune cells, activating and sensitizing primary afferent nociceptors (nociceptive pain) and damaging the nervous system (neuropathic pain).
For a great review please see Dr. Kara’s curation The Genetics of Pain: An Integrated Approach.
Palliative Care
For a good review please see the following LINK on Palliative Care
Palliative Care_4.6
Please See VIDEOs on Cancer, Pain and Palliative Care
From ACS Guideline: Developing a plan for pain control
The first step in developing a pain control plan is talking with your cancer care team about your pain. You need to be able to describe your pain to your family or friends, too. You may want to have your family or friends help you talk to your cancer care team about your pain, especially if you’re too tired or in too much pain to talk to them yourself.
Using a pain scale is a helpful way to describe how much pain you’re feeling. To use the Pain Intensity Scale shown here, try to assign a number from 0 to 10 to your pain level. If you have no pain, use a 0. As the numbers get higher, they stand for pain that’s getting worse. A 10 means the worst pain you can imagine.
| 0 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 |
| No pain | Worst pain |
For instance, you could say, “Right now, my pain is a 7 on a scale of 0 to 10.”
You can use the rating scale to describe:
- How bad your pain is at its worst
- What your pain is like most of the time
- How bad your pain is at its least
- How your pain changes with treatment
Tell your cancer care team and your family or friends:
- Where you feel pain
- What it feels like – for instance, sharp, dull, throbbing, gnawing, burning, shooting, steady
- How strong the pain is (using the 0 to 10 scale)
- How long it lasts
- What eases the pain
- What makes the pain worse
- How the pain affects your daily life
- What medicines you’re taking for the pain and how much relief you get from them
NCCN Adult Cancer-Associated Pain Guidelines (see PDF)NCCN adult pain guidelines
NCCN gives a comprehensive guideline to Cancer Patient Pain Management for Caregivers, physicians, and educational materials for patients.
The attached PDF gives information on
- Pain Definition and Pain Management Principles
- Pain Screening, Rating and Assessment Guidelines
- Management of Patients with Differing Opioid Tolerance
- Opioid Titration Guidelines
- Adjuvant Analgesia
- Psychosocial Support
Table. Important Points in NCCN Guidelines for Pain Management
| Pain Severity (pain scale level) | guideline |
| All pain levels | – Opioid maintenance, – psychosocial support, – caregiver education |
| Severe Pain (7-10) | – Reevaluate opioid titration |
| Moderate (4-6) | – Continue opioid titration
– Consider specific pain syndrome problem and consultation – continue analgesic titration |
| Mild (0-3) | Adjuvant analgesics |
The clinical presentation of cancer pain depends on the histologic type of cancer, the location of the primary neoplasm, and location of metastases. (for example pain in breast cancer patients have different pain issues than patients with oral.cancer).
However, high grade serous ovarian cancer, the most clinically prevalent of this disease, usually presents as an ascitic carcinomatosis, spread throughout the peritoneum and mesothelium.
Ovarian cancer stem cells and mediators of pain
Although not totally accepted by the field, a discussion of ovarian cancer stem cells is warranted, especially in light of this discussion. Cancer stem cells are considered that subpopulation of cells in the bulk tumor exhibiting self-renewing capacity, generally resistant to chemotherapy, and therefore repopulate the tumor with new tumor cells. In this case, ovarian cancer stem cells could be more pertinent to the manifestations of pain than bulk tumor, as these cells would survive chemotherapy. This may be the case, as ovarian cancer pain may not be associated with overall tumor burden? Are there PAIN MEDIATORS secreted from ovarian cancer cells?
Some Known Pain Mediators Secreted from Ovarian Tumor Cells
Endothelin-1
- Local injection of endothelin-1 produces pain-like behavior and excitation of nociceptors in rats. Gokin AP, Fareed MU, Pan HL, Hans G, Strichartz GR, Davar G J Neurosci. 2001 Jul 15; 21(14):5358-66.
- Expression and localization of endothelin receptors: implications for the involvement of peripheral glia in nociception.Pomonis JD, Rogers SD, Peters CM, Ghilardi JR, Mantyh PW J Neurosci. 2001 Feb 1; 21(3):999-1006.
- Endothelin and the tumorigenic component of bone cancer pain.[Neuroscience. 2004]
- Endothelin-1 induces tumor proteinase activation and invasiveness of ovarian carcinoma cells. Rosanò L1, Varmi M, Salani D, Di Castro V, Spinella F, Natali PG, Bagnato A. Cancer Res. 2001 Nov 15;61(22):8340-6.
- Endothelin-1 is required during epithelial to mesenchymal transition in ovarian cancer progression. Rosanò L1, Spinella F, Di Castro V, Decandia S, Nicotra MR, Natali PG, Bagnato A. Exp Biol Med (Maywood). 2006 Jun;231(6):1128-31.
Proteases and Protease-Activated Receptors
Hoogerwerf WA, Zou L, Shenoy M, Sun D, Micci MA, Lee-Hellmich H, Xiao SY, Winston JH, Pasricha PJ
J Neurosci. 2001 Nov 15; 21(22):9036-42.
Alier KA, Endicott JA, Stemkowski PL, Cenac N, Cellars L, Chapman K, Andrade-Gordon P, Vergnolle N, Smith PA.J Pharmacol Exp Ther. 2008 Jan; 324(1):224-33.
- Serine proteases and protease-activated receptor 2-dependent allodynia: a novel cancer pain pathway. Lam DK, Schmidt BL. Pain. 2010 May; 149(2):263-72.
- Differential expression of protease activated receptor 1 (Par1) and pY397FAK in benign and malignant human ovarian tissue samples. Grisaru-Granovsky S, Salah Z, Maoz M, Pruss D, Beller U, Bar-Shavit R. Int J Cancer. 2005 Jan 20;113(3):372-8.
Bradykinin
Sevcik MA, Ghilardi JR, Halvorson KG, Lindsay TH, Kubota K, Mantyh PW
J Pain. 2005 Nov; 6(11):771-5
- T-kinin in human ovarian carcinoma ascites. Adv Exp Med Biol. 1989;247B:109-14. Wunderer G1, Walter I.
Nerve Growth Factor
- Nerve growth factor expression correlates with perineural invasion and pain in human pancreatic cancer.[J Clin Oncol. 1999]
- Role of nerve growth factor and FSH receptor in epithelial ovarian Bose CK. Reprod Biomed Online. 2005 Aug;11(2):194-7. Review.
Tumor Necrosis Factor
- Nociceptive characteristics of tumor necrosis factor-alpha in naive and tumor-bearing mice. Wacnik PW, Eikmeier LJ, Simone DA, Wilcox GL, Beitz AJ Neuroscience. 2005; 132(2):479-91.
- Autocrine self-elimination of cultured ovarian cancer cells by tumour necrosis factor alpha (TNF-alpha). Simonitsch I, Krupitza G. Br J Cancer. 1998 Oct;78(7):862-70.
Opioids: A Reference
Opioid analgesics: analgesia without loss of consciousness
Three main uses of opioids
- Analgesia
- Antitussive
- Diarrhea
1954 – nalorphine, partial antagonists had analgesic effect. Morphine: Morpheus – Greek God of dreams
1) opiates: opium alkaloids including morphine, codeine, thebaine, papavarine
2) synthetic: meperedine, methadone
Chemistry
- Antagonist properties associated with replacement of the methyl substituent on nitrogen atom with large group (naloxone and nalorphine replaced with allyl group)
- Pharmacokinetic properties affected by C3 and C6 hydroxyl substitutions
- CH3 at phenolic OH at C3 reduces first pass metabolism by glucoronidation THEREFORE codeine and oxycodeine have higher oral availability
- Acetylation of both OH groups on morphine : heroin penetrates BBB : rapidly hydrolyzed to give monoacetylmorphine and morphine
Pharmaookinetics
- Well absorbed from s.c., i.m., oral
- Codeine and hydrocodeine higher absorption from oral:parental ratio because of extensive first pass metabolism
- Most opioids are well absorbed orally but DECREASE potency due to first pass
- Variable plasma protein binding
- Brain distribution is actually low but opioids are very potent
- Well distributed and may accumulate in skeletal muscle
- Fentynyl (lipophilic) may accumulate in fat
Metabolism
- Most opioids converted to polar metabolites so excreted by kidney ;IMPORTANT prolonged analgesia in patients with renal disease
- Esters like meperidine and herion metabolized by tissue esterases
- Glucoronidated morphine may have analgesic properties
Receptors
All three (mu, kappa, and delta) activate pertussis toxin sensitive G protein {Gi}
Opioids quiet pain (nociceptive) neurons by inhibiting nerve conduction (decrease entry of calcium or increase entry of potassium)
There are four major subtypes of opioid receptors:[12]
| Receptor | Subtypes | Location[13][14] | Function[13][14] |
| delta (δ) DOR OP1 (I) |
δ1,[15] δ2 |
|
|
| kappa (κ) KOR OP2 (I) |
κ1, κ2, κ3 |
|
|
| mu (μ) MOR OP3 (I) |
μ1, μ2, μ3 |
|
μ1:
μ2: μ3:
|
| Nociceptin receptor NOP OP4 |
ORL1 |
|
Tolerance and Physical Dependence
Tolerance: gradual loss of effectiveness over repeated doses
Physical Dependence: when tolerance develops continued administration of drug required to prevent physical withdrawal symptoms
- With opioids see tolerance most with the analgesic, sedative, and antitussive effects; not so much with antidiarrheal effects
Major effects of opioids on Organ Systems
- CNS
- Analgesia – raise threshhold for pain
- Euphoria – pleasant floating feeling but sometimes dysphoria (agitation)
- Sedation –drowsiness but no amnesia; more frequent in elderly than young but can disrupt normal REM sleep
- Respiratory depression – ALL opioids produce significant resp. depression by inhibiting the brain stem; careful in patients with impaired respiratory function like COPD or increased intracranial pressure
- Cough suppression – tolerance can develop; may increase airway secretions
- Miosis – constriction of pupils; seen with ALL agonists; treat with atropine
- Rigidity – mostly seen with fentanyl; treat with opioid antagonist like nalozone
- Emesis; naseua, vomiting
- Peripheral
- Cardiovascular – no real major effects; some specific compounds may have effects on blood pressure
- GI – Constipation most common; loperamide (Immodium); pentazocine may cause less constipation; problem for treating cancer patients for pain; opioid receptors do exist in the GI tract but effect may be CNS as well as local
- Biliary system – minor, may cause constriction of bile duct
- GU (genitourinary) – reduced urine output by increased antidiuretic hormone
- Uterus – may prolong labor
- Neuroendocrine – opioid analgesics can stimulate release of ADH, prolactin
- Other – opioid analgesics may cause flushing and warming of skin; release of histamine?
Specific Agents
Strong Agonists
- Phenanthrenes –all are used for analgesia
- Morphine –
- Hydromorphone
- Oxymorphone
- Heroin
- Phenylheptylamine
- Methadone – longer acting than morphine; tolerance and physical dependency slower to develop than with morphine; low doses of methadone may be used for heroin addict undergoing withdrawal
- Phenyllpiperidines
- Meperidine
- Fentanyl (also sufentanil) which is 5-7 more times potent than fentanyl. Negative inotropic (contractile force) effects on heart
- Levorphanol
Mild to Moderate Agonist
- Phenanthrenes – most given in combo with NSAID
- Codeine – antitussive, some analgesia
- Oxycodone
- Dihydrocodone
- Hydrocodone
- Propoxyphene – Darvon, low abuse and low analgesia compared to morphine
- Phenylpiperidines
- Diphenoxylate –used for diarrhea; not for analgesia and no abuse potential
- Loperamide – antidiarrheal (Imodium), low abuse potential
Mixed Agonist-Antagonist & Partial Agonists
- Nalbulphine – strong kappa agonist and mu antagonist.. Analgesic
- Buprenorphine – analgesic. Partial mu agonist has long duration. Slow dissocation from receptor makes resistant to naloxone reversal
- Buterphanol – analgesia with sedation, kappa agonist
- Pentazocine – kappa agonist with weak mu antagonism.Is an irritant so do no inject s.c.
Antagonists
- Naloxone – quick reversal of opioid agonist action (1-2 hours); not well absorbed orally; pure antagonist so no effects by itself; no tolerance problems; opioid antidote
- Naltrexone – well absorbed orally can be used in maintenance therapy because of long duration of action
Antitussives
- Codeine
- Dextromethorphan
- Levoproposyphen
- Noscapine
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