Introduction
The American Cannabis Nurses Association supports the monitored and controlled use of cannabis in conjunction with opiate administration for patients (either human or animal) who are suffering from severe pain, intractable pain, severe neuropathy or pain associated with terminal illness. Additionally, any patient on long-term opiate therapy should be evaluated for cannabis therapy to lessen the risk of adverse events associated with opiates. This position is justified by the evidence base of use patterns, the in-vitro research demonstrating the interaction of endocannabinoid receptors with opiate receptors, the potential severity of adverse events associated with long-term opiate use and the ethical responsibility of health care practitioners to advocate on behalf of their patients.

Pain and Conventional Treatments
Pain is the neurological process that provides internal communication via nerve cells indicating an injury or disease. Pain is a cardinal symptom of many disease processes especially if it is associated with tissue or organ nerve damage.

Pain impulses are carried through nerve fibers which are present in all tissues and organs, and exist in huge numbers in the central nervous system. The CNS is composed of the spinal cord and the brain. The peripheral nervous system (PNS) contains nerves located in the arms, legs, skin and other parts of the body outside the brain and spinal cord. Neurotransmitters like serotonin, dopamine, adrenalin and glutamate, are released by receptors in the cell, in response to specific nerve impulses which trigger their activity. The anatomy of a nerve cell is arranged in order to carry sensory impulses from one cell to another and into the brain and motor impulses from the brain back to a specific area.

There are many different qualities and types of pain. Pain may also be non-physical in nature, arising from psychological trauma or mental illness. Phantom limb pain, for instance, is the perception of pain in an appendage (arm or leg) which has been amputated. Intractable pain is excruciating pain which is unresponsive to medical or pharmacologic interventions.

Analgesics are a class of drugs which (are intended to) block or reduce the movement of pain signals to the brain, reducing the perception of pain. There are many different types of analgesics- including opiates- which treat many different types and intensities of pain. Prescribers attempt to match the analgesic to the pain in the lowest effective dose. As the severity of the pain increases, so does the potency of the drug prescribed. Severe pain, by definition, is pain which defies easy control. The pain cycle often results in escalating doses of one pharmaceutical, until it fails to adequately control the pain or the side effects become excessive. This is followed by a different and more potent analgesic. The side effects and toxicities increase in proportion.

Patient's suffering from severe pain- like migraines, neuropathy or cancer, present a huge challenge to prescribers because the pain continues often for the patient's entire life and involve potentially lethal doses of analgesics over a long time period. Large doses of opiates additionally render many patients unable to effectively function, further reducing quality of life.

Morphine is considered the standard for the most severe pain. It comes in many forms and dosages and combinations with other agents which are meant to synergistically work with the morphine at lower doses. Morphine activates specific receptors which release endorphins. It has very potent central nervous system activity, blocking pain signals in the brain. It can also depress the vital functions of the CNS, like breathing. High doses of morphine can also impair liver function and sensory function and result in constipation. From 1999 to 2010, the number of U.S. drug poisoning deaths involving any opioid analgesic (e.g., oxycodone, methadone, or hydrocodone) more than quadrupled, from 4,030 to 16,651 per year, accounting for 43% of the 38,329 drug poisoning deaths and 39% of the 42,917 total poisoning deaths in 2010.(1)

Analgesic Properties of Cannabis
Cannabis is effective as an analgesic due to its potent CB₁ receptor binding activity in both peripheral and central nervous system nerve pathways. When inhaled, it rapidly crosses the blood brain barrier. Researchers have demonstrated that cannabinoids reduce hyperalgesia- or increased sensitivity to pain- through activation of CB₁ receptors at the site of injury.(2) Endocannabinoid receptor activity represents a parallel, separate, but interconnected pain modulation system with the opioid receptor system in the CNS.(3,4,5) The foundation of the endocannabinoid system is the activity of CB₁ and CB₂ receptors which cause the release (or inhibit) a complex cascade of endocrine, hormonal or cellular chemicals from the brain or tissues themselves. This is the "homeostatic regulatory function" of the endocannabinoid system which help patients "relax, eat, sleep, forget and protect"(6). CB₁ receptors are mainly located in the brain and CB₂ receptors are located throughout the body in enormous numbers, especially immune system tissues. Cannabinoid receptors may be activated either by the internal endocannabinoid signaling process with anandamide or 2-AG (arachidonyl glycerol)- which all mammals synthesize- or activated through the administration of exogenous cannabinoids found in the cannabis plant. In essence, the cannabis plant has co-evolved over millions of years with humans to produce homeostatic regulatory chemicals nearly identical to those humans and animals produce themselves.

The neurochemical receptor binding actions of cannabinoids have been described in detail through animal modeling experiments. Cannabinoids interact with serotonergic, dopaminergic, glutaminergic, opioid neurotransmitters, and inflammatory processes. ∆-9-THC reduces serotonin release from the platelets of humans suffering migraine thus inhibiting the pain signals triggered by serotonin.

Clinical considerations with cannabis and opioid co-administration
Any patient suffering from serious pain conditions should be evaluated for cannabis use. Many analgesics are combined with synergistic compounds in order to decrease the total dose of the most powerful one- usually morphine or codeine. Cannabis is no exception. A clinician whose patient is requesting or using cannabis should consider the patient's total pain management program especially the total dosage of opiates, muscle relaxants (flexeril) or benzodiazepines in long-term pain management and the adverse experiences, if any, resulting from high doses. (Documentation of changes in prescription amounts over time after initiating cannabis treatment is easily accomplished. Examination of previous prescription records presents an opportunity to retrospectively determine the therapeutic value of cannabis if the clinician knows when the patient began using it.) Patient's commonly report a decrease of opiate use from 1/3 to ½ as well as increased functional ability. Some patients eliminate the use of opiates nearly completely. There is no documented data indicating that concurrent use of opiates and cannabis increases adverse outcomes.

Adverse events and contraindications from cannabis/cannabinoids do occur. Most significantly, worsening or precipitation of psychosis. Anxiety or panic reactions may sometimes occur to naive users or patients ingesting substantial doses by mouth. There is no known lethal overdose recorded. Additionally, cannabis (like opiates) may mask underlying diseases. It may also adversely influence the metabolism of other drugs the patient may be using. Cannabis has a long history of use as a harm-reduction substitute for addiction to other substances. Co-occurring substance abuse may or may not be a contraindication to the use of cannabis. A detailed understanding of pharmacological, medical and social circumstances will provide guidance to clinicians. Cannabis Hyperemesis Syndrome has been documented in a small number of long-term cannabis users. Users report colicky abdominal pain, recurring nausea and vomiting, with symptom resolution upon abstinence. The etiology of this disorder is unknown and the occurrence is rare.

Clinician guidelines should include evaluating the risks and benefits of all treatments relative to one another (as well as presence and severity of co morbid substance abuse). Clinician guidelines should not include coercive drug tests based solely on a patient's report of cannabis use. The standardized use of detailed "pain contracts" with mandatory- or unannounced- drug screens should be reserved for only those patients who have significant compliance issues which have been demonstrated over time. The general use of coercive pain contracts undermines the patient's trust in the physician and fosters miscommunication and deception. "Agreements" (as opposed to contracts) with patient's to monitor and document analgesic use over time with the addition of cannabis allows a working relationship with the prescriber which fosters trust.

In the event that a patient's drug screen indicates the presence of cannabinoid metabolites, an enlightened health care provider will engage in a detailed discussion with the patient in order to determine the underlying reason for the use of cannabis and if it is improving the quality of life of the person. A patient's report that he/she "feels better" after they use cannabis should not be detrimental, since the homeostatic regulatory functions of cannabis generally improve comfort.

The refusal of a clinician to discuss with or seriously evaluate the use of cannabis specifically in relation to that person's underlying medical diagnoses violates the clinicians' practice guidelines which include detailed evaluation of the patient's condition through an educated understanding of the complexity of their circumstances and knowledge of different treatments.

Cannabis has been used as an analgesic for 5000 years.(7) As restrictive laws give way to sensible regulation, its use as a medicine will increase, because patients are unable or unwilling to tolerate potent pharmaceuticals, or cannot afford them. All clinicians should be undertaking an education in endocannabinoid therapeutics in order to gain the understanding of this complex system. Clinicians should also understand route-dependant metabolism, federal and state legal barriers, strain evaluation processes, safe handling considerations, research advancements, novel cannabinoid drug development and dosing options- like vaporizers.

The American Medical Association's Code of Medical Ethics, Opinion 1.02 - The Relation of Law and Ethics(8) reads, in part:

"Ethical values and legal principles are usually closely related, but ethical obligations typically exceed legal duties. In some cases, the law mandates unethical conduct." "In exceptional circumstances of unjust laws, ethical responsibilities should supersede legal obligations."

The federal ban of the use of medical cannabis by patients may be interpreted as an ethical dilemma for physicians, compounded by the DEA prescriptive authority which may be revoked, rendering the clinician incapable of practice. Physicians and Nurse Practitioners must weigh these factors. The unwillingness of federal legislators and regulators on all levels to change the scheduling of cannabis represents an unconscionable and inhumane obstacle to cannabis patients, researchers and clinicians. Ethical principles of medical practice require clinicians to work actively to eliminate these injustices and advocate for an intelligent federal policy which does not victimize suffering people and waste tax revenues in the process.

Endocannabinoid therapeutics represents a subspecialty of medicine. The guidelines of clinical practice require "evidence- based" practice resting on the principles of science and ethics. Endocannabinoid therapeutics has evolved to the point where it meets these requirements of practice.

Sources

1. National Vital Statistics System. Mortality data. http://www.cdc.gov/nchs/deaths.htm

2. Richardson, et al, Cannabinoids Reduce Hyperalgesia and Inflamation via interaction with peripheral CB-1 receptors. Pain 75, 1998 111-119.

3. Welch SP: Interaction of the cannabinoid and opioid systems in the modulation of nociception. Int Rev Psychiatry 2009, 21:143-51.

4. J, Beaulieu P: Opioids and cannabinoids interactions: involvement in pain management. Curr Drug Targets 2010, 11:462-73.

5. Lucas, P., Cannabis as an Adjunct to or Substitute for Opiates in the Treatment of Chronic Pain. Journal of Psychoactive Drugs Volume 44, Issue 2, 2012, DOI: 10.1080/02791072.2012.684624.

6. Di Marzo, Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action, Trends Neurosci. 1998 21, 521–528.

7. Russo E., The Role of Cannabis and Cannabinoids in Pain Management, Weiner's Pain Management, Seventh Edition, 2006, 823-843.

8. American Medical Association: Code of Medical Ethics. Opinion 1.02-The Relation of Law and Ethics. http://www.ama-assn.org/ama/pub/physician-resources/medical-ethics/code-medical-ethics/opinion102.page?

Alabama: Considering a medical marijuana law.
   HB642 - The Michael Phillips Compassionate Care Act of Alabama

Arkansas: Considering a medical marijuana law.

Florida: Medical marijuana petition drive underway.

Idaho: Considering a medical marijuana law.

Illinois: Passed a medical marijuana law.
   House Committee Passes Medical Marijuana Pilot Program

Indiana: Considering a medical marijuana law.

Iowa: Considering a medical marijuana law.

Kansas: Medical marijuana petition drive underway.
   Marijuana Bill Reaches House
   Cannabis Compassion and Care Act

Maryland: Considering a medical marijuana law.
   Medical Marijuana Approved by Maryland House of Delegates

Minnesota: Considering a medical marijuana law.

Missouri: Considering a medical marijuana law.
   HOUSE BILL NO. 1670 - An Act relating to the use of marijuana for medicinal purposes
   Cottleville Mayor Don Yarber hopes Missouri legislature passes medical marijuana law

New Hampshire: Passed a medical marijuana law.
   New Hampshire Poised to Legalize Medical Marijuana

New York: Considering a medical marijuana law.
   Medical Marijuana Bills Introduced

North Carolina: Considering a medical marijuana law.
   North Carolina Medical Cannabis Act

Ohio: Considering a medical marijuana law.
   HB 214

Pennsylvania: Considering a medical marijuana law.
   HB 1393

South Carolina: Considering a medical marijuana law.

South Dakota: Medical marijuana petition drive underway.

Tennessee: Considering a medical marijuana law.

Texas: Considering a medical marijuana law.

Many patients who utilize and benefit from medical cannabis do not wish to smoke due to the perceived health hazards of smoking or for other personal reasons. These patients are in something of a bind. Smoking cannabis delivers the active cannabinoids within seconds. Medicine is absorbed in the lungs and goes directly to the brain and general circulation. The same effect can be achieved with a vaporizer, which is safer than smoking burning vegetable matter. Since the effects of inhaled cannabis are so quick, it is easy for patients to titrate their dose by simply waiting a minute or two in between puffs.

Oral cannabis, such as our Better Bud Butter, is absorbed in a very different fashion from smoking or inhalation. The GI tract gradually absorbs Cannabinoids over the course of one to two hours. Medicine is processed first by the liver, which converts some cannabinoids such as delta nine to delta 11 version of THC. Orally delivered cannabis requires four to ten times the amount of the smoked version in order to achieve the same effect. Orally delivered cannabis can present a problem in achieving the required or desired dose level in any consistent fashion.

Tincture is designed to address the problems of rapid medicine delivery and consistent dosing. Most tinctures are made to be used under the tongue or sublingually. English pharmaceutical companies are presently working on a cannabis extract "spray" that can be used under the tongue in a similar fashion. These sprays are not expected to be approved for use in the United States for years and will be very expensive. Absorption by the arterial blood supply under the tongue is completed in seconds. One trick is to not swallow the dose as, if swallowed, absorption will be in the GI tract. Many patients, though, add their tincture to a cup of tea or cranberry juice for easy delivery. When tincture is used in a beverage, absorption will be slower than if absorbed under the tongue. While tincture absorbed in an empty stomach is accomplished in minutes, conversion in the liver remains, as does the difficulty in titrating dose. Usually, a tincture dose is delivered by means of a medicine dropper or a teaspoon. A rule of thumb on dose is that patients receive benefit from 3-4 drops to a couple of full droppers depending upon the potency of the tincture and the patient’s own unique requirements among other factors.

The methods listed below will detail two major methods of preparing tincture. While the methods are optimized for purity and potency, ultimately these will largely be determined by the purity and potency of the cannabis from which the tincture is made. Another item of note in regard to starting material for tincture is the patient or caregiver selection of strain. A rough rule of thumb is to select Indica dominant strains for cramping and muscle spasticity and Sativa dominant strains for pain relief. The reality, though, is often that the strain is unknown or not well characterized. Trial and error is usually required to acquire the appropriate strain and the proper dose level.

General Rules:

Tincture is an extraction of active cannabinoids from plant material. Cannabis contains many chemicals that can either upset the stomach or taste nasty. One of the goals of extraction is to secure the cannabinoids while leaving out as many of the terpenes and chlorophylls as possible. Both heat and light adversely effect cannabinoids and should be avoided or minimized. Tincture should be stored in airtight dark glass containers kept at room temperature or below. Avoid plastic containers. The ethanol in the tincture may solubilize some of the free vinyls in the plastic.

Making tincture cold preserves the integrity of cannabinoids. To be potent, this method requires starting material high in cannabinoid content such as flowers or kief made from trim and leaf. The material must be mold free and dry. Drying can be accomplished in the freezer (-4-10 degrees Celsius) or better yet by placing in a liquid proof bag into a dry ice/ethanol ice bath (-70 degrees Celsius). Once water has been removed then the surface area of the starting material requires expansion. This can be accomplished a number of ways but two ways stand out:

Using flowers (bud)- Place dried buds in a coffee grinder and pulse until thoroughly ground but not powdered.

Making kief- Rub dry trim and leaves over a silk screen. Collect the powder the comes through the screen. It should be a very pale green. "Kiefing" is an age old way of extracting trichomes from plant material.

Whether kief or ground bud is used both should kept ice cold for this preparation. Similarly, the ethanol to be used should also be ice cold throughout the process.

Selection of alcohol- ethanol or ethyl alcohol is the form of alcohol that can be used by humans. The proof listed on commercial alcohol refers to the percentage of ethanol that the beverage contains. The proof is twice the percentage, so 80 "proof" means that the mixture contains 40% ethanol. The higher the alcohol content used, the better the extraction will work. Ideally, 200 proof ethanol would be best except that ethanol cannot be distilled to this proof so benzene is used to remove the last vestiges of water. This makes "pure" ethanol poisonous.

Many folks use "Everclear" which stands at 190 proof or 95% ethanol. Everclear has no taste. Apparently, Everclear is not available in all States. A close second choice is 151 proof rum. This is a light amber liquid that is 75% ethanol that has a sweet taste. One of our caregiver writers will use nothing but Korbel brandy because she likes the taste. Others use iced Russian vodka. These "normal" distilled spirits are 40% to 50% ethanol. Some patients find that the higher proofs ethanols like Everclear and 151 rum burn too much under the tongue. If burning is a concern consider a high quality 90-100 proof Vodka.

Cold Extraction and purification- Use at least one ounce of starting material to each pint of ethanol. Place cold powdered kief or ground cannabis flowers together with ethanol in a glass quart-mixing jar. Close the jar tightly and vigorously shake for five minutes then return to the freezer. Continue to agitate the mixture every few hours with refreezing. Continue for a period of two to three days.

Pour the cold mixture through a double thickness of sterile cheesecloth. Save the cheesecloth "ball" for topical uses or use the material to make bud butter once dried. The liquid collected through the cheesecloth should then be filtered twice through a paper coffee filter. Use gloves throughout the process, as it is necessary to squeeze the cheesecloth and coffee filters to facilitate the extraction. Without gloves some of the material will be absorbed on the skin.

If Everclear is used the tincture will be pale green to golden. If 151 rum is used an amber tincture results. Dark green tinctures mean that excess plant material is present. This does not mean that the tincture will not be potent, just taste nasty. When Everclear is used, various flavor extracts may be added (vanilla, raspberry, etc.). Be careful to use only a few drop of flavor extract.

Place the ethanol and chopped cannabis in a large glass Mason jar. Shake at least once a day. Place the jar in a brown paper bag or otherwise shield the jar from light. Leave in a warm spot (near a window) for 30-60 days. The mixture will turn a very dark green. Strain as previously described through cheesecloth. Save the "shake ball" for topical applications.

While this method produces a nasty tasting tincture, it is powerful. It may upset some fragile stomachs. It is recommended that Warm Tincture be used orally in cranberry juice or coffee with sugar. Keep the filtered tincture in light blocking glass jars or bottles in a cool dry place (refrigerator or freezer is fine). The shake ball should also be kept in the freezer. For topical applications, just take out the cold shake ball and apply a few drops of fresh tincture to the cloth then hold it on the affected area for a few minutes with gentle rubbing.