Doctors are being advised not to prescribe common painkillers, including paracetamol and ibuprofen, for patients with chronic pain not caused by an injury or other medical condition.
The National Institute of Health and Care Excellence (NICE) said there was little evidence they help.
And it suggests there is evidence long-term use can be harmful.
Its draft guidance recommends antidepressants, acupuncture or psychological therapy instead.
The advisory body also strongly advises against the use of opioids for these patients, in a set of guidelines covering England, Wales and Northern Ireland.
It said there was a "lack of evidence" for the effectiveness of opioids for this condition, along with a risk of long-term harm.
Chronic primary pain is defined within the guidelines as a condition which "can't be accounted for by another diagnosis".
This type of unexplained pain may affect as many as between a third and half of people in the UK, the guidelines estimate.
These are the first NICE guidelines to address primary pain as a condition in itself.
There was no evidence paracetamol was effective in treating people for whom pain was their primary problem, the committee developing the guidelines said.
And the family of drugs that includes ibuprofen "made no difference to people's quality of life, pain or psychological distress".
Both medicines came with the risk of possible harm, including stomach and liver damage.
The committee also did not recommend cannabis-based medicines, since there is so far not enough evidence for their effectiveness.
Instead, doctors could consider prescribing an antidepressant or a course of acupuncture.
They could also consider recommending a course of cognitive therapy, aimed at helping patients accept their condition or change the way they thought about it.
This marked a "stark move from pharmacological therapies to alternative therapies," according to the Royal College of GPs.
Prof Martin Marshall, RCGP chair, said: "Most patients in pain do not want to take medication long-term, and GPs do not want this either, but sometimes medication has been the only thing that brings relief.
"As such these new guidelines, which focus on alternative therapies, have the potential to be beneficial for patients - but they will need to be guaranteed appropriate access to them."
NICE also highlighted the importance of doctors communicating honestly but sensitively with patients.
The guidelines acknowledged there is a lot of uncertainty in this diagnosis, and "normal or negative test results can be communicated in a way that is perceived as being dismissive of pain".
When it comes to chronic pain more broadly - defined as pain that "persists or recurs" for more than three months, no matter the cause - NICE advises using these new guidelines alongside existing guidance on the management of specific conditions.
That includes headaches, back pain, arthritis and endometriosis.
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